Prodrugs of GABA analogs, compositions and uses thereof

ABSTRACT

The present invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods for making prodrugs of GABA analogs. The present invention also provides methods for using prodrugs of GABA analogs and methods for using pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders.

This application is a continuation of and claims the benefit under 35U.S.C. § 120 from U.S. patent application Ser. No. 10/171,485, filedJun. 11, 2002 now U.S. Pat. No. 6,818,787, which claimed the benefitunder 35 U.S.C. § 119(e) from U.S. Provisional Application Ser. No.60/297,521 filed Jun. 11, 2001; U.S. Provisional Application Ser. No.60/298,514 filed Jun. 14, 2001; and U.S. Provisional Application Ser.No. 60/366,090 filed Mar. 19, 2002. The above applications are hereinincorporated by reference in their entirety.

1. FIELD OF THE INVENTION

The present invention relates generally to prodrugs of GABA analogs,pharmaceutical compositions of to prodrugs of GABA analogs, methods ofmaking prodrugs of GABA analogs, methods of using prodrugs of GABAanalogs and pharmaceutical compositions of prodrugs of GABA analogs.More particularly, the present invention relates to prodrugs ofgabapentin and pregabalin, pharmaceutical compositions of prodrugs ofgabapentin and pregabalin, methods of making prodrugs of gabapentin andpregabalin, methods of using prodrugs of gabapentin and pregabalin andpharmaceutical compositions of prodrugs of gabapentin and pregabalin.

2. BACKGROUND OF THE INVENTION

Gamma (“γ”)-aminobutyric acid (“GABA”) is one of the major inhibitorytransmitters in the central nervous system of mammals. GABA is nottransported efficiently into the brain from the bloodstream (i.e., GABAdoes not effectively cross the blood-brain barrier). Consequently, braincells provide virtually all of the GABA found in the brain (GABA isbiosynthesized by decarboxylation of glutamic acid with pyridoxalphosphate).

GABA regulates neuronal excitability through binding to specificmembrane proteins (i.e., GABAA receptors), which results in opening ofan ion channel. The entry of chloride ion through the ion channel leadsto hyperpolarization of the recipient cell, which consequently preventstransmission of nerve impulses to other cells. Low levels of GABA havebeen observed in individuals suffering from epileptic seizures, motiondisorders (e.g., multiple sclerosis, action tremors, tardivedyskinesia), panic, anxiety, depression, alcoholism and manic behavior.

The implication of low GABA levels in a number of common disease statesand/or common medical disorders has stimulated intensive interest inpreparing GABA analogs, which have superior pharmaceutical properties incomparison to GABA (e.g., the ability to cross the blood brain barrier).Accordingly, a number of GABA analogs, with considerable pharmaceuticalactivity have been synthesized in the art (See, e.g., Satzinger et al.,U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat. No. 5,563,175;Horwell et al., U.S. Pat. No. 6,020,370; Silverman et al., U.S. Pat. No.6,028,214; Horwell et al., U.S. Pat. No. 6,103,932; Silverman et al.,U.S. Pat. No. 6,117,906; Silverman, International Publication No. WO92/09560; Silverman et al., International Publication No. WO 93/23383;Horwell et al., International Publication No. WO 97/29101, Horwell etal., International Publication No. WO 97/33858; Horwell et al.,International Publication No. WO 97/33859; Bryans et al., InternationalPublication No. WO 98/17627; Guglietta et al., International PublicationNo. WO 99/08671; Bryans et al., International Publication No. WO99/21824; Bryans et al., International Publication No. WO 99/31057;Belliotti et al., International Publication No. WO 99/31074; Bryans etal., International Publication No. WO 99/31075; Bryans et al.,International Publication No. WO 99/61424; Bryans et al., InternationalPublication No. WO 00/15611; Bryans, International Publication No. WO00/31020; Bryans et al.,

International Publication No. WO 00/50027; and Bryans et al.,International Publication No. WO 02/00209).

Pharmaceutically important GABA analogs include, for example, gabapentin(1), pregabalin (2), vigabatrin (3), and baclofen (4) shown above.Gabapentin is a lipophilic GABA analog that can pass through theblood-brain barrier, which has been used to clinically treat epilepsysince 1994. Gabapentin also has potentially useful therapeutic effectsin chronic pain states (e.g., neuropathic pain, muscular and skeletalpain), psychiatric disorders (e.g., panic, anxiety, depression,alcoholism and manic behavior), movement disorders (e.g., multiplesclerosis, action tremors, tardive dyskinesia), etc. (Magnus, Epilepsia,1999, 40:S66-S72). Currently, gabapentin is also used in the clinicalmanagement of neuropathic pain. Pregabalin, which possesses greaterpotency in pre-clinical models of pain and epilepsy than gabapentin ispresently in Phase III clinical trials.

A significant problem with many GABA analogs is intramolecular reactionof the γ amino group with the carboxyl functionality to form theγ-lactam, as exemplified for gabapentin below. Formation of γ-lactam (5)presents serious difficulties in formulating gabapentin because of itstoxicity. For example, gabapentin has a toxicity (LD₅₀, mouse) of morethan 8000 mg/kg, while the corresponding lactam (5) has a toxicity(LD₅₀, mouse) of 300 mg/kg. Consequently, formation of side productssuch as lactams during synthesis of GABA analogs and/or formulationand/or storage of GABA analogs or compositions of GABA analogs must beminimized for safety reasons (particularly, in the case of

gabapentin).

The problem of lactam contamination of GABA analogs, particularly in thecase of gabapentin, has been partially overcome through use of specialadditional purification steps, precise choice of adjuvant materials inpharmaceutical compositions and careful control procedures (Augurt etal., U.S. Pat. No. 6,054,482). However, attempts to prevent lactamcontamination have not been entirely successful, in either synthesis orstorage of GABA analogs such as gabapentin or compositions thereof.

Rapid systemic clearance is another significant problem with many GABAanalogs including gabapentin, which consequently require frequent dosingto maintain a therapeutic or prophylactic concentration in the systemiccirculation (Bryans et al., Med. Res. Rev., 1999, 19, 149-177). Forexample, dosing regimens of 300-600 mg doses of gabapentin administeredthree times per day are typically used for anticonvulsive therapy.Higher doses (1800-3600 mg/d in divided doses) are typically used forthe treatment of neuropathic pain states.

Sustained released formulations are a conventional solution to theproblem of rapid systemic clearance, as is well known to those of skillin the art (See, e.g., “Remington's Pharmaceutical Sciences,”Philadelphia College of Pharmacy and Science, 17th Edition, 1985).Osmotic delivery systems are also recognized methods for sustained drugdelivery (See, e.g., Verma et al., Drug Dev. Ind. Pharm., 2000,26:695-708). Many GABA analogs, including gabapentin and pregabalin, arenot absorbed via the large intestine. Rather, these compounds aretypically absorbed in the small intestine by the large neutral aminoacid transporter (“LNAA”) (Jezyk et al., Pharm. Res., 1999, 16,519-526). The rapid passage of conventional dosage forms through theproximal absorptive region of the gastrointestinal tract has preventedthe successful application of sustained release technologies to manyGABA analogs.

Thus, there is a significant need for effective sustained releaseversions of GABA analogs to minimize increased dosing frequency due torapid systemic clearance of these compounds. There is also a need forpure GABA analogs, (particularly gabapentin and pregablin analogs) whichare substantially pure and do not spontaneously lactamize during eitherformulation or storage.

3. SUMMARY OF THE INVENTION

The present invention addresses these and other needs by providingprodrugs of GABA analogs, pharmaceutical compositions of prodrugs ofGABA analogs and methods for making prodrugs of GABA analogs. Thepresent invention also provides methods for using prodrugs of GABAanalogs, and methods for using pharmaceutical compositions of prodrugsof GABA analogs for treating or preventing common diseases and/ordisorders.

Importantly, the prodrugs provided by the present invention may possesssignificant pharmaceutical advantages of particular use in medicine.First, the promoiety of the prodrugs of GABA analogs provided by thecurrent invention are typically labile in vivo (i.e., cleaved by eitherenzymatic or chemical means to generate substantial quantities of a GABAanalog before the prodrug is cleared from a patient. Second, thepromoiety derivative provided by cleavage of the promoiety from theprodrug, and any metabolite thereof, is typically non-toxic whenadministered to a mammal in accordance with dosing regimens typicallyfollowed with the GABA analog.

The compounds of the instant invention have a promoiety attached to theγ amino group of GABA analogs. This promoiety may be directly attachedto the γ amino group of a GABA analog, or optionally may be attached tothe amino group of an α-amino acid promoiety, or to the hydroxy group ofan α-hydroxy acid promoiety, which itself is attached to the γ aminogroup of the GABA analog.

The compounds of the invention may also have a promoiety attached to thecarboxyl group of GABA analogs. The carboxyl promoiety will typically bean ester or thioester group. A wide variety of ester or thioester groupsmay be used to form carboxyl promoieties.

Accordingly, the compounds of the invention may include as many as fourpromoieties, including one carboxyl promoiety and up to three aminopromoieties attached in sequence to the γ amino group (i.e., such thateach promoiety is sequentially cleaved from the N-terminal end of theGABA analog). The compounds of the invention may contain two aminopromoieties and one carboxyl promoiety, two amino promoieties, one aminopromoiety and one carboxyl promoiety or one amino promoiety. Preferably,in those compounds of the invention which contain both an aminopromoiety and a carboxyl promoiety, the carboxyl promoiety is hydrolyzedprior to the complete cleavage of the promoiety (ies) attached to theamine group.

In a first aspect, the present invention provides compounds of Formula(I), Formula (II) or Formula (III):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein:

m, n, t and u are independently 0 or 1;

X is O or NR¹⁶;

W is O or NR¹⁷;

Y is O or S;

R¹ is selected from the group consisting of hydrogen, R²⁴C(O)—,R²⁵OC(O)—, R²⁴C(S)—, R²⁵OC(S)—, R²⁵SC(O)—, R²⁵SC(S)—, (R⁹O)(R¹⁰O)P(O)—,R²⁵S—,

each R² is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substitutedacyl, acylamino, substituted acylamino, alkylamino, substitutedalkylamino, alklysulfinyl, substituted alkylsulfinyl, alkylsulfonyl,substituted alkylsulfonyl, alkylthio, substituted alkylthio,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy,carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino,halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy andsubstituted heteroaryloxy, or optionally, R² and R¹⁶ together with theatoms to which they are attached form a cycloheteroalkyl or substitutedcycloheteroalkyl ring;

R³ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl andsubstituted heteroarylalkyl or optionally, R⁴ and R⁵ together with thecarbon atom to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridgedcycloalkyl ring;

R⁸ and R¹² are independently selected from the group consisting ofhydrogen, acyl, substituted acyl, alkoxycarbonyl, substitutedalkoxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl, or optionally R⁸ and R¹² together with thecarbon atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R¹¹ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cyano, cycloalkyl,substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, alkoxycarbonyl, substituted alkoxycarbonyl,cycloheteroalkyloxycarbonyl, substituted cycloheteroalkyloxycarbonyl,aryloxycarbonyl, substituted aryloxycarbonyl, heteroaryloxycarbonyl,substituted heteroaryloxycarbonyl and nitro;

R⁷, R⁹, R¹⁰, R¹⁵, R¹⁶ and R¹⁷ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl and substituted heteroarylalkyl;

R¹³ and R¹⁴ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkylor optionally, R¹³ and R¹⁴ together with the carbon atom to which theyare attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkylor substituted cycloheteroalkyl ring;

R²⁰ and R²¹ are independently selected from the group consisting ofhydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl oroptionally R²⁰ and R²¹ together with the carbon atom to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

R²² and R²³ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyland substituted arylalkyl or optionally, R²² and R²³ together with thecarbon atom to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R²⁴ is selected from the group consisting of hydrogen, acyl, substitutedacyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; and

R²⁵ is selected from the group consisting of acyl, substituted acyl,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl.

In a second aspect, the present invention provides pharmaceuticalcompositions of compounds of the invention. The pharmaceuticalcompositions generally comprise one or more compounds of the invention,and a pharmaceutically acceptable vehicle.

In a third aspect, the present invention provides methods for treatingor preventing epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain (especially, neuropathic pain and muscular and skeletalpain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders or ethanol withdrawal syndrome. The methodsgenerally involve administering to a patient in need of such treatmentor prevention a therapeutically effective amount of a compound of theinvention.

In a fourth aspect, the current invention provides pharmaceuticalcompositions for treating or preventing epilepsy, depression, anxiety,psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, pain (especially, neuropathic painand muscular and skeletal pain), inflammatory disease (i.e., arthritis),insomnia, gastrointestinal disorders or ethanol withdrawal syndrome in apatient in need of such treatment or prevention. The methods generallyinvolve administering to a patient in need of such treatment orprevention a therapeutically effective amount of a pharmaceuticalcomposition of the invention.

In a fifth aspect, the invention comprises a GABA analog derivativecompound, M-G, for administration to a patient in need of therapy,wherein M is a promoiety and G is derived from a GABA analog, H-G (whereH is hydrogen). The promoiety M, once cleaved from G, and any metabolitethereof, exhibits a carcinogenically toxic dose (TD₅₀) in rats ofgreater than 0.2 mmol/kg/day. Further, the promoiety M cleaves from G ata sufficient rate in vivo, upon colonic administration to rats, toproduce:

-   -   (i) a maximum concentration of H-G in plasma (C_(max)) of at        least 120% of the C_(max) of H-G in plasma is achieved by        colonically administering an equimolar dose of H-G; and    -   (ii) an AUC that is at least 120% of the AUC is achieved by        colonically administering an equimolar dose of H-G.

Preferably, M-G is a derivative of Formula (XIV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein:

R is hydrogen or R and R⁶ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring; and

Y, R³, R⁴, R⁵, R⁶ and R⁷ are as previously defined.

Most preferably, M is a derivative of Formula (XV):

wherein

n, X, R¹ and R² are as previously defined.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Definitions

“Active transport or active transport process” refers to the movement ofmolecules across cellular membranes that:

a) is directly or indirectly dependent on an energy mediated process(i.e., driven by ATP hydrolysis, ion gradient, etc.);

or

b) occurs by facilitated diffusion mediated by interaction with specifictransporter proteins.

“Alkyl” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. Preferably, an alkyl group comprisesfrom 1 to 20 carbon atoms, more preferably, from 1 to 10 carbon atoms.

“Alkanyl” refers to a saturated branched, straight-chain or cyclic alkylradical derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. Typical alkanyl groups include, but are notlimited to, methanyl; ethanyl; propanyls such as propan-1-yl,propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such asbutan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon double bond derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkene. The group may be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicalkyl radical having at least one carbon-carbon triple bond derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such asbut-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acylamino” (or alternatively “acylamido”) refers to a radical—NR′C(O)R, where R′ and R are each independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein. Representative examples include, butare not limited to, formylamino, acetylamino (i.e., acetamido),cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino(i.e., benzamido), benzylcarbonylamino and the like.

“Acyloxy” refers to a radical —OC(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroarylor heteroarylalkyl, as defined herein. Representative examples include,but are not limited to, acetyloxy (or acetoxy), butyloxy (or butoxy),benzoyloxy and the like.

“Alkylamino” means a radical —NHR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylamino, ethylamino, 1-methylethylamino,cyclohexyl amino and the like.

“Alkoxy” refers to a radical —OR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy andthe like.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is asdefined herein.

“Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

“Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

“Alkylthio” refers to a radical —SR where R is an alkyl or cycloalkylgroup as defined herein that may be optionally substituted as definedherein. Representative examples include, but are not limited tomethylthio, ethylthio, propylthio, butylthio and the like.

“Amino” refers to the radical —NH₂.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Preferably, an arylgroup comprises from 6 to 20 carbon atoms, more preferably between 6 to12 carbon atoms.

“Arylalkyl” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl and/or arylalkynyl is used. Preferably, anarylalkyl group is (C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₁₀) and the aryl moiety is(C₆-C₂₀), more preferably, an arylalkyl group is (C₆-C₂₀) arylalkyl,e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is(C₁-C₈) and the aryl moiety is (C₆-C₁₂).

“Arylalkyloxy” refers to an —O-arylalkyl group where arylalkyl is asdefined herein.

“Aryloxycarbonyl” refers to a radical —C(O)—O-aryl where aryl is asdefined herein.

“AUC” is the area under the plasma drug concentration-versus-time curveextrapolated from zero time to infinity.

“Bridged cycloalkyl” refers to a radical selected from the groupconsisting of

wherein:

A is (CR³⁵R³⁶)_(b);

R³⁵ and R³⁶ are independently selected from the group consisting ofhydrogen and methyl;

R³³ and R³⁴ are independently selected from the group consisting ofhydrogen and methyl;

b is an integer from 1 to 4; and

c is an integer from 0 to 2.

“Carbamoyl” refers to the radical —C(O)N(R)₂ where each R group isindependently hydrogen, alkyl, cycloalkyl or aryl as defined herein,which may be optionally substituted, as defined herein.

“Carboxy” means the radical —C(O)OH.

“Carcinogenic potency (TD₅₀)” (see Peto et al., Environmental HealthPerspectives 1984, 58, 1-8) is defined for a particular compound in agiven animal species as that chronic dose-rate in mg/kg body wt/daywhich would induce tumors in half the test animals at the end of astandard lifespan for the species. Since the tumor(s) of interest oftendoes occur in control animals, TD₅₀ is more precisely defined as: thatdose-rate in mg/kg body wt/day which, if administered chronically forthe standard lifespan of the species, will halve the probability ofremaining tumorless throughout that period. A TD₅₀ can be computed forany particular type of neoplasm, for any particular tissue, or for anycombination of these.

“C_(max)” is the highest drug concentration observed in plasma followingan extravascular dose of drug.

“Compounds of the invention” refers to compounds encompassed by genericformulae disclosed herein and includes any specific compounds withinthat formula whose structure is disclosed herein. The compounds of theinvention may be identified either by their chemical structure and/orchemical name. When the chemical structure and chemical name conflict,the chemical structure is determinative of the identity of the compound.The compounds of the invention may contain one or more chiral centersand/or double bonds and therefore, may exist as stercoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds of theinvention may also exist in several tautomeric forms including the enolform, the keto form and mixtures thereof. Accordingly, the chemicalstructures depicted herein encompass all possible tautomeric forms ofthe illustrated compounds. The compounds of the invention also includeisotopically labeled compounds where one or more atoms have an atomicmass different from the atomic mass conventionally found in nature.Examples of isotopes that may be incorporated into the compounds of theinvention include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl. Further, it should be understood, whenpartial structures of the compounds of the invention are illustrated,that brackets indicate the point of attachment of the partial structureto the rest of the molecule.

“Composition of the invention” refers to at least one compound of theinvention and a pharmaceutically acceptable vehicle, with which thecompound is administered to a patient. When administered to a patient,the compounds of the invention are administered in isolated form, whichmeans separated from a synthetic organic reaction mixture.

“Cyano” means the radical —CN.

“Cycloalkyl” refers to a saturated or unsaturated cyclic alkyl radical.Where a specific level of saturation is intended, the nomenclature“cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groupsinclude, but are not limited to, groups derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane, and the like. Preferably, thecycloalkyl group is (C₃-C₁₀) cycloalkyl, more preferably (C₃-C₇)cycloalkyl.

“Cycloheteroalkyl” refers to a saturated or unsaturated cyclic alkylradical in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Where a specific level of saturation isintended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl”is used. Typical cycloheteroalkyl groups include, but are not limitedto, groups derived from epoxides, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

“Cycloheteroalkyloxycarbonyl” refers to a radical —C(O)—OR where R iscycloheteroalkyl is as defined herein.

“Derived from a bile acid” refers to a moiety that is structurallyrelated to a compound of Formulae (XVII) or (XVIII):

wherein each of D, E and F are independently H or OH.

The structure of the moiety is identical to the compounds above exceptat 1 or 2 positions. At these positions, a hydrogen atom attached to ahydroxyl group and/or the hydroxyl moiety of the carboxylic acid grouphas been replaced with a covalent bond that serves as a point ofattachment to another moiety, which is preferably a GABA analog or GABAanalog derivative.

“Derived from a GABA analog” refers to a moiety that is structurallyrelated to a GABA analog. The structure of the moiety is identical tothe compound except at 1 or 2 positions. At these positions, a hydrogenatom attached to the amino group, and (optionally) the hydroxyl moietyof the carboxylic acid group has been replaced with a covalent bond thatserves as a point of attachment to another moiety.

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl or cycloalkyl group as defined herein. Representativeexamples include, but are not limited to, dimethylamino,methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino and the like.

“GABA analog” refers to a compound, unless specified otherwise, ashaving the following structure:

wherein:

R is hydrogen, or R and R⁶ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring;

R³ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl; and

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl or optionally, R⁴ and R⁵ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkylring.

“Halo” means fluoro, chloro, bromo, or iodo.

“Heteroalkyloxy” means an —O-heteroalkyl group where heteroalkyl is asdefined herein.

“Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl” refer toalkyl, alkanyl, alkenyl and alkynyl radical, respectively, in which oneor more of the carbon atoms (and any associated hydrogen atoms) are eachindependently replaced with the same or different heteroatomic groups.Typical heteroatomic groups include, but are not limited to, —O—, —S—,—O—O—, —S—S—, —O—S—, —NR′—, ═N—N═, —N═N—, —N═N—NR′—, —PH—, —P(O)₂—,—O—P(O)₂—, —S(O)—, —S(O)₂—, —SnH₂— and the like, where R′ is hydrogen,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl orsubstituted aryl.

“Heteroaryl” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. Preferably, the heteroarylgroup is between 5-20 membered heteroaryl, more preferably between 5-10membered heteroaryl. Preferred heteroaryl groups are those derived fromthiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole and pyrazine.

“Heteroaryloxycarbonyl” refers to a radical —C(O)—OR where R isheteroaryl as defined herein.

“Heteroarylalkyl” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heteroaryl group. Where specific alkylmoieties are intended, the nomenclature heteroarylalkanyl,heteroarylalkenyl and/or heterorylalkynyl is used. In preferredembodiments, the heteroarylalkyl group is a 6-30 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of theheteroarylalkyl is 1-10 membered and the heteroaryl moiety is a5-20-membered heteroaryl, more preferably, 6-20 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of theheteroarylalkyl is 1-8 membered and the heteroaryl moiety is a5-12-membered heteroaryl.

“Passive diffusion” refers to uptake of an agent that is not mediated bya specific transporter protein. An agent that is substantially incapableof passive diffusion has a permeability across a standard cell monolayer(e.g., Caco-2) in vitro of less than 5×10⁻⁶ cm/sec, and usually lessthan 1×10⁻⁶ cm/sec (in the absence of an efflux mechanism).

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention, which is pharmaceutically acceptable and possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Patient” includes humans. The terms “human” and “patient” are usedinterchangeably herein.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, —X, —R²⁹, —O⁻, ═O,—OR²⁹, —SR²⁹, —S⁻, ═S, —NR²⁹R³⁰, ═NR²⁹, —CX₃, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)²OH, —S(O)₂R²⁹, —OS(O₂)O⁻,—OS(O)₂R²⁹, —P(O)(O⁻)₂, —P(O)(OR²⁹)(O⁻), —OP(O)(OR²⁹)(OR³⁰), —C(O)R²⁹,—C(S)R²⁹, —C(O)OR²⁹, —C(O)NR²⁹R³⁰, —C(O)O⁻, —C(S)OR²⁹, —NR³¹C(O)NR²⁹R³⁰,—NR³¹C(S)NR²⁹R³⁰, —NR³¹C(NR²⁹)NR²⁹R³⁰ and —C(NR²⁹)NR²⁹R³⁰, where each Xis independently a halogen; each R²⁹ and R³⁰ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NR³¹R³², —C(O)R³¹ or —S(O)₂R³¹ or optionally R²⁹ andR³⁰ together with the atom to which they are both attached form acycloheteroalkyl or substituted cycloheteroalkyl ring; and R³¹ and R³²are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl.

“Transporter protein” refers to a protein that has a direct or indirectrole in transporting a molecule into and/or through a cell. For example,a transporter protein may be, but is not limited to, solute carriertransporters, co-transporters, counter transporters, uniporters,symporters, antiporters, pumps, equilibrative transporters,concentrative transporters and other proteins, which mediate activetransport, energy-dependent transport, facilitated diffusion, exchangemechanisms and specific absorption mechanisms. Transporter proteins, mayalso be, but are not limited to, membrane-bound proteins that recognizea substrate and effect its entry into or exit from a cell by acarrier-mediated transporter or by receptor-mediated transport. Atransporter protein, may also be, but is not limited to, anintracellularly expressed protein that participates in trafficking ofsubstrates through or out of a cell. Transporter proteins, may also be,but are not limited to, proteins or glycoproteins exposed on the surfaceof a cell that do not directly transport a substrate but bind to thesubstrate holding it in proximity to a receptor or transporter proteinthat effects entry of the substrate into or through the cell. Examplesof carrier proteins include: the intestinal and liver bile acidtransporters, dipeptide transporters, oligopeptide transporters, simplesugar transporters (e.g., SGLT1), phosphate transporters,monocarboxcylic acid transporters, P-glycoprotein transporters, organicanion transporters (OAT), and organic cation transporters. Examples ofreceptor-mediated transport proteins include: viral receptors,immunoglobulin receptors, bacterial toxin receptors, plant lectinreceptors, bacterial adhesion receptors, vitamin transporters andcytokine growth factor receptors.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the patient. In yet another embodiment, “treating” or“treatment” refers to inhibiting the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, etc., of the patient to be treated.

Reference will now be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction with thepreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, modifications, and equivalents as maybe included within the spirit and scope of the invention as defined bythe appended claims.

4.2 The Compounds of the Invention

Those of skill in the art will appreciate that compounds of Formulae(I), (II) and (III) share certain structural features in common. Thesecompounds are all GABA analogs (i.e., γ-aminobutryic acid derivatives)to which promoieties have been attached. In particular, R², R³, R⁴, R⁵,R⁶, X and Y are common substituents found in compounds of Formulae (I),(II) and (III).

The compounds of the invention include compounds of Formula (I), Formula(II) or Formula (III):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein:

n, t, u, X, Y, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R²⁰, R²¹, R²² and R²³ are aspreviously defined above.

In a preferred embodiment, compounds of Formulae (I), (II) and (III) donot include the following compounds:

when R³ and R⁶ are both hydrogen, then R⁴ and R⁵ are not both hydrogenand are not both methyl;

in a compound of Formula (I) when either n is 0 or when n is 1 and X isNR¹⁶, then R¹ is not hydrogen;

in a compound of Formula (I) neither R¹, R⁷O—, R²⁴C(O)—, R²⁵C(O)— norR²⁵O— is a moiety derived from a bile acid;

in a compound of Formula (I) when R¹ is R²⁴C(O)— and n is 0, then R²⁴ isnot methyl, tert-butyl, 2-aminoethyl, 3-aminopropyl, benzyl, phenyl or2-(benzoyloxymethyl)phenyl;

in a compound of Formula (I) when R¹ is R²⁵OC(O)—, then R²⁵ is notR²⁶C(O)CR¹³R¹⁴—, wherein R²⁶ is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl;

in a compound of Formula (I) when R¹ is R²⁵OC(O)— and n is 0, then R²⁵is not methyl, tert-butyl or benzyl;

in a compound of Formula (I) when n is 0 and R¹ is R²⁵C(O)CR¹³R¹⁴OC(O)—then if either R¹³ or R¹⁴ is hydrogen, alkoxycarbonyl, substitutedalkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substitutedcycloalkoxycarbonyl, the other of R¹³ or R¹⁴ is not hydrogen;

in a compound of Formula (I) when n is 1, X is NH, R³, R⁵ and R⁶ areeach hydrogen, and R⁴ is cyclohexyl, then R² is not benzyl;

in a compound of Formula (II) when t is 1, u is 0, then neither R²⁰ norR²¹ is 2-hydroxy-3-methyl-5-chlorophenyl; and

in a compound of Formula (II) when u is 1 and X is O, then t is 1.

In one embodiment of compounds of Formulae (I), (II) and (III), when R³and R⁶ are each hydrogen, then R⁴ and R⁵ are neither both hydrogen norboth methyl. In one embodiment of compounds of Formula (I), when eithern is 0 or when n is 1 and X is NR¹⁶, then R¹ is not hydrogen. In anotherembodiment, of compounds of Formula (I), neither R¹, R⁷O—, R²⁴C(O)—,R²⁵C(O)— nor R²⁵O— is a moiety derived from a bile acid. In stillanother embodiment of compounds of Formula (I), when R¹ is R²⁴C(O)— andn is 0, then R²⁴ is not alkyl, substituted alkyl, arylalkyl, aryl orsubstituted aryl. In still another embodiment of compounds of Formula(I), when R¹ is R²⁴C(O)— and n is 0, then R²⁴ is not C₁₋₄ alkanyl,benzyl, phenyl or substituted phenyl. In still another embodiment ofcompounds of Formula (I), when R¹ is R²⁴C(O)— and n is 0, then R²⁴ isnot methyl, tert-butyl, 2-aminoethyl, 3-aminopropyl, benzyl, phenyl or2-(benzoyloxymethyl)-phenyl. In still another embodiment of compounds ofFormula (I) when R¹ is R²⁵OC(O)—, then R²⁵ is not R²⁶C(O)CR¹³R¹⁴—. Instill another embodiment of compounds of Formula (I) when R¹ isR²⁵OC(O)— and n is 0, then R²⁵ is not alkyl or arylalkyl. In stillanother embodiment of compounds of Formula (I) when R¹ is R²⁵OC(O)— andn is 0, then R²⁵ is not C₁₋₄ alkanyl or benzyl. In still anotherembodiment of compounds of Formula (I) when R¹ is R²⁵OC(O)— and n is 0,then R²⁵ is not methyl, tert-butyl or benzyl. In still anotherembodiment of compounds of Formula (I) when n is 0 and R¹ isR²⁵C(O)OCR¹³R¹⁴OC(O)— then if either R¹³ or R¹⁴ is hydrogen,alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl,cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, the other of R¹³or R¹⁴ is not hydrogen. In still another embodiment of compounds ofFormula (I) when R³, R⁵ and R⁶ are each hydrogen, then R⁴ is notcyclohexyl. In still another embodiment of compounds of Formula (I) whenn is 1, X is NH, R³, R⁵, R⁶ are each hydrogen and R² is benzyl, then R⁴is not cyclohexyl.

In one embodiment of compounds of Formula (II), neither R²⁰ nor R²¹ is2-hydroxy-3-methyl-5-chlorophenyl. In one embodiment of compounds ofFormula (II), when u is 1 and X is O, then t is 1.

In one embodiment of compounds of Formulae, (I) (II) and (III), n is 0.In another embodiment, n is 1. When n is 1, and X is NR¹⁶, preferablythe α-amino acid is of the L-stereochemical configuration.

In another embodiment of compounds of Formulae (I) and (II), R⁷ isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl,cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl andsubstituted cycloheteroalkanyl. In a preferred embodiment, Y is O and R⁷is hydrogen. In still another embodiment, Y is O and R⁷ is alkanyl,substituted alkanyl, alkenyl, substituted alkenyl, aryl or substitutedaryl. Preferably, R⁷ is methyl, ethyl, benzyl, —C(CH₃)═CH₂,—CH₂C(O)N(CH₃)₂,

where V is O or CH₂.

In one preferred embodiment of compounds of Formulae (I), (II) and(III), R² is selected from the group consisting of hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl. Preferably, R² is selected from the group consistinghydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl andsubstituted heteroarylalkanyl.

In another embodiment compounds of Formulae (I), (II) and (III), X is NHand R² is hydrogen, cycloalkanyl or alkanyl. Preferably, R² is hydrogen,methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl orcyclohexyl. In another embodiment, X is NH and R² is substitutedalkanyl. Preferably, R² is —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂. In still another embodiment, X is NH and R² isselected from the group consisting of aryl, arylalkanyl, substitutedarylalkanyl and heteroarylalkanyl. Preferably, R² is phenyl, benzyl,4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl or 2-indolyl. In yetanother embodiment, X is NR¹⁶ and R² and R¹⁶ together with the atoms towhich they are attached form a cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably R² and R¹⁶ together with the atoms towhich they are attached form an azetidine, pyrrolidine or piperidinering.

In still another embodiment of compounds of Formulae (I), (II) and(III), R³ is hydrogen. In still another embodiment, R⁶ is hydrogen. Inyet another embodiment, R³ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, cycloalkyl and substituted cycloalkyl. Preferably, R³and R⁶ are independently selected from the group consisting of hydrogenand alkanyl. More preferably, R³ is hydrogen or alkanyl and R⁶ ishydrogen.

In still another preferred embodiment of compounds of Formulae (I), (II)and (III), R⁴ and R⁵ are independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl and substitutedcycloheteroalkyl. Preferably, R⁴ and R⁵ are independently selected fromthe group consisting of hydrogen, alkanyl and substituted alkanyl.

In another embodiment of compounds of Formulae (I), (II) and (III), R⁴and R⁵ together with the carbon atom to which they are attached form acycloalkanyl or substituted cycloalkanyl ring. Preferably, R⁴ and R⁵together with the carbon atom to which they are attached form acyclobutyl, substituted cyclobutyl, cyclopentyl, substitutedcyclopentyl, cyclohexyl or substituted cyclohexyl ring. In anotherembodiment, R⁴ and R⁵ together with the carbon atom to which they areattached form a cycloheteroalkyl or substituted cycloheteroalkyl ring.In still another embodiment, R⁴ and R⁵ together with the carbon atom towhich they are attached form a bridged cycloalkyl ring.

In one embodiment of compounds of Formula (I), n is 1, R¹ is R²⁴C(O)— orR²⁴C(S)— and R²⁴ is alkyl, substituted alkyl, heteroalkyl, substitutedheteroalkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl. Preferably, R²⁴ is methyl, ethyl, 2-propyl, t-butyl,—CH₂OCH(CH₃)₂, phenyl or 3-pyridyl.

In another embodiment of compounds of Formula (I), n is 1, R¹ isR²⁵OC(O)— or R²⁵SC(O)— and R²⁵ is alkyl, substituted alkyl, heteroalkyl,aryl, substituted aryl, heteroaryl or substituted heteroaryl.Preferably, R²⁵ is ethyl, 2-propyl, neopentyl, —CH₂OCH(CH₃)₂, phenyl or2-pyridyl.

One preferred embodiment of compounds of Formula (I) includes compoundsof Formula (IV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein:

n, Y, R², R³, R⁴, R⁵, R⁶, R⁷, R¹³, R¹⁴, R¹⁶ and R²⁵ are as previouslydefined.

In a preferred embodiment, the compounds of Formula (IV), do not includethe following compounds:

when either R¹³ or R¹⁴ is hydrogen, alkoxycarbonyl, substitutedalkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substitutedcycloalkoxycarbonyl, then the other of R¹³ or R¹⁴ is not hydrogen; and

R²⁵C(O) is not a moiety derived from a bile acid.

In one embodiment of compounds of Formulae (IV), R¹³ and R¹⁴ areindependently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl,arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl or heteroaryl (preferably, when R¹³ isalkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R¹⁴ is methyl).More preferably, R¹³ and R¹⁴ are independently hydrogen, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl,cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl or 3-pyridyl.

In another embodiment of compounds of Formula (IV), R¹³ and R¹⁴ areindependently hydrogen, alkanyl, substituted alkanyl, cycloalkanyl orsubstituted cycloalkanyl. Preferably, R¹³ and R¹⁴ are hydrogen, alkanylor cycloalkanyl. More preferably, R¹³ and R¹⁴ are independentlyhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopentyl or cyclohexyl. Even more preferably, R¹³ ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopentyl or cyclohexyl and R¹⁴ is hydrogen, or R¹³ ismethyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formula (IV), R¹³ and R¹⁴are independently hydrogen, aryl, arylalkyl or heteroaryl. Morepreferably, R¹³ and R¹⁴ are independently hydrogen, phenyl, benzyl,phenethyl or 3-pyridyl. Even more preferably, R¹³ is phenyl, benzyl,phenethyl or 3-pyridyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formula (IV), R¹³ and R¹⁴are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,carbamoyl, or cycloalkoxycarbonyl. Preferably, when R¹³ isalkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R¹⁴ is methyl.More preferably, R¹³ is methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl and R¹⁴is methyl.

In still another embodiment of compounds of Formula (IV), R¹³ and R¹⁴together with the carbon atom to which they are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring. Preferably, R¹³ and R¹⁴ together with the carbonatom to which they are attached form a cycloalkyl ring. More preferably,R¹³ and R¹⁴ together with the carbon atom to which they are attachedform a cyclobutyl, cyclopentyl or cyclohexyl ring.

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl. Preferably, R²⁵ is acyl, substituted acyl,alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl.More preferably, R²⁵ is methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl.

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl orsubstituted acyl. More preferably, R¹⁵ is acetyl, propionyl, butyryl,benzoyl or phenacetyl.

In still another embodiment of compounds of Formula (IV), R²⁵ is alkanylor substituted alkanyl. Preferably, R²⁵ is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl or1-(1,3-dioxan-2-yl)-2-phenethyl. More preferably, R²⁵ is methyl, ethyl,propyl, isopropyl, butyl, 1,1-dimethoxyethyl or 1,1-diethoxyethyl.

In still another embodiment of compounds of Formula (IV), R²⁵ is aryl,arylalkyl or heteroaryl. Preferably, R²⁵ is phenyl, 4-methoxyphenyl,benzyl, phenethyl, styryl or 3-pyridyl.

In still another embodiment of compounds of Formula (IV), R²⁵ iscycloalkyl or substituted cycloalkyl. More preferably R²⁵ iscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; and R¹³ and R¹⁴ are independently hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substitutedcycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably,when R¹³ is alkoxycarbonyl, substituted alkoxycarbonyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl thenR¹⁴ is methyl). Preferably, R²⁵ is acyl, substituted acyl, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ andR¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl,cycloalkoxycarbonyl or heteroaryl (preferably, when R¹³ isalkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl,substituted cycloalkoxycarbonyl or carbamoyl then R¹⁴ is methyl). Morepreferably, R²⁵ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl and R¹³ and R¹⁴ are independentlyhydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl or 3-pyridyl. Even more preferably, R²⁵ is methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1,1-dimethoxybenzyl,1,1-diethoxybenzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, cyclohexyl or 3-pyridyl, and R¹³ andR¹⁴ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl.

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl and R¹³ and R¹⁴ together with the atom towhich they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably, R²⁵is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl,cycloalkyl or heteroaryl and R¹³ and R¹⁴ together with the atom to whichthey are attached form a cycloalkyl or substituted cycloalkyl ring. Morepreferably, R²⁵ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl, and R¹³ and R¹⁴ together with theatom to which they are attached form a cyclobutyl, cyclopentyl or acyclohexyl ring.

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl orsubstituted acyl and R¹³ and R¹⁴ are independently hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substitutedcycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably,when R¹³ is alkoxycarbonyl, substituted alkoxycarbonyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl thenR¹⁴ is methyl). Preferably, R²⁵ is acetyl, propionyl, butyryl, benzoylor phenacetyl, and R¹³ and R¹⁴ are independently hydrogen, alkyl,substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substitutedcycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably,when R¹³ is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R¹⁴ ismethyl).

In still another embodiment of compounds of Formula (IV), R²⁵ is alkanylor substituted alkanyl and R¹³ and R¹⁴ are independently hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substitutedcycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably,when R¹³ is alkoxycarbonyl, substituted alkoxycarbonyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl thenR¹⁴ is methyl). Preferably, R²⁵ is methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl or 1-(1,3-dioxan-2-yl)-2-phenethyl,and R¹³ and R¹⁴ are independently hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substitutedcycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl,heteroaryl or substituted heteroaryl (preferably, when R¹³ isalkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl then R¹⁴ is methyl).

In still another embodiment of compounds of Formula (IV), R²⁵ is aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl orsubstituted heteroaryl, and R¹³ and R¹⁴ are independently hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substitutedcycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably,when R¹³ is alkoxycarbonyl, substituted alkoxycarbonyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl thenR¹⁴ is methyl). Preferably R²⁵ is phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl or 3-pyridyl and R¹³ and R¹⁴ are independentlyhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl orsubstituted heteroaryl (preferably, when R¹³ is alkoxycarbonyl,cycloalkoxycarbonyl or carbamoyl then R¹⁴ is methyl).

In still another embodiment of compounds of Formula (IV), R²⁵ iscycloalkyl or substituted cycloalkyl, and R¹³ and R¹⁴ are independentlyhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl orsubstituted heteroaryl (preferably, when R¹³ is alkoxycarbonyl,substituted alkoxycarbonyl, cycloalkoxycarbonyl, substitutedcycloalkoxycarbonyl or carbamoyl then R¹⁴ is methyl). Preferably, R²⁵ iscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and R¹³ and R¹⁴ areindependently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl orsubstituted heteroaryl (preferably, when R¹³ is alkoxycarbonyl,cycloalkoxycarbonyl or carbamoyl then R¹⁴ is methyl).

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl, and R¹³ and R¹⁴ are independently hydrogen,alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl.Preferably, R²⁵ is acyl, substituted acyl, alkyl, substituted alkyl,aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ and R¹⁴ areindependently hydrogen, alkanyl, substituted alkanyl, cycloalkanyl orsubstituted cycloalkanyl. More preferably, R²⁵ is acyl, substitutedacyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl orheteroaryl and R¹³ and R¹⁴ are independently hydrogen, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentylor cyclohexyl. In the above embodiments, R²⁵ is preferably methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxbutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkylor heteroaryl and R¹³ and R¹⁴ are independently hydrogen, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl.Preferably, R²⁵ is acyl, substituted acyl, alkyl, substituted alkyl,aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ and R¹⁴ areindependently hydrogen, aryl, arylalkyl or heteroaryl. More preferably,R²⁵ is acyl, substituted acyl, alkyl, substituted alkyl, aryl,arylalkyl, cycloalkyl or heteroaryl and R¹³ and R¹⁴ are independentlyhydrogen, phenyl, benzyl, phenethyl or 3-pyridyl. In the aboveembodiments, R²⁵ is preferably methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl.

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkylor heteroaryl and R¹³ and R¹⁴ are independently hydrogen, alkyl,substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl.Preferably, R²⁵ is acyl, substituted acyl, alkyl, substituted alkyl,aryl, arylalkyl, cycloalkyl or heteroaryl and R¹³ and R¹⁴ areindependently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl,substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl orsubstituted cycloalkoxycarbonyl (preferably, when R¹³ is alkoxycarbonyl,substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl orsubstituted cycloalkoxycarbonyl then R¹⁴ is methyl; more preferably, R¹³is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl or cyclohexyloxycarbonyl, and R¹⁴ is methyl). In theabove embodiments, R²⁵ is preferably methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl,1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl,1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl,1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl,1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl,1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl,1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl,1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl,acetyl, propionyl, butyryl, benzoyl, phenacetyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or 3-pyridyl.

In still another embodiment of compounds of Formula (IV), R²⁵ is acyl,substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkylor heteroaryl and R¹³ and R¹⁴ together with the atom to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. Preferably, R²⁵ is acyl, substitutedacyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl orheteroaryl and R¹³ and R¹⁴ together with the atom to which they areattached form a cycloalkyl or substituted cycloalkyl ring. Morepreferably R²⁵ is acyl, substituted acyl, alkyl, substituted alkyl,aryl, arylalkyl, cycloalkyl or heteroaryl, and R¹³ and R¹⁴ together withthe atom to which they are attached form a cyclobutyl, cyclopentyl orcyclohexyl ring. In the above embodiments, R²⁵ is preferably methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In still another embodiment of compounds of Formulae (I) and (III), R¹is

m is 0, and R⁸, R¹¹ and R¹² are as previously defined.

In one embodiment of compounds of Formulae (I) and (III), R¹¹ is acyl,alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R⁸ ishydrogen, alkoxycarbonyl, alkyl, aryl, arylalkyl or cyano and R¹² ishydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, or arylalkyl.

In another embodiment of compounds of Formulae (I) and (III), R¹¹ isselected from the group consisting of acetyl, propionyl, butyryl,isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl,benzoyl, phenacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, cyclopentyloxycarbonyl,cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl,N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl,N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopentylcarbamoyl,N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl,N,N-diisopropylcarbamoyl, N,N-dibutylcarbamoyl, N,N-dibenzylcarbamoyl,N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl andN-morpholinylcarbamoyl. More preferably, R¹¹ is selected from the groupconsisting of acetyl, propionyl, butyryl, isobutyryl,cyclohexanecarbonyl, benzoyl, phenacetyl, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl,N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N-isopropylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl,N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl,N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl andN-morpholinylcarbamoyl.

In still another embodiment of compounds of Formulae (I) and (III), R⁸is selected from the group consisting of hydrogen, methyl, ethyl,propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl,benzyloxycarbonyl and cyano. More preferably R⁸ is selected from thegroup consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl,methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In still another embodiment of compounds of Formulae (I) and (III), R¹²is selected from the group consisting of hydrogen, methyl, ethyl,propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl andbenzyloxycarbonyl. More preferably R¹² is selected from the groupconsisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl,methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In still another embodiment of compounds of Formulae (I) and (III), R¹¹is selected from the group consisting of hydrogen, alkoxycarbonyl,alkyl, substituted alkyl, aryl, arylalkyl and R⁸ and R¹² together withthe carbon atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring. Preferably, R¹¹ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl,ethoxycarbonyl and butoxycarbonyl, and R⁸ and R¹² together with thecarbon atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Morepreferably, R¹¹ is hydrogen or methyl and R⁸ and R¹² together with thecarbon atoms to which they are attached form a cyclopent-1-ene,cyclohex-1-ene, 2-cyclopenten-1-one, 2-cyclohexen-1-one, 2-(5H)-furanoneor 5,6-dihydro-pyran-2-one ring.

In still another embodiment of compounds of Formulae (I) and (III), R¹²is selected from the group consisting of hydrogen, alkoxycarbonyl,alkyl, substituted alkyl, aryl, arylalkyl and R⁸ and R¹¹ together withthe carbon atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring. Preferably, R¹² is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl,ethoxycarbonyl and butoxycarbonyl, and R⁸ and R¹¹ together with thecarbon atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Morepreferably, R¹² is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl,ethoxycarbonyl and butoxycarbonyl, and R⁸ and R¹¹ together with thecarbon atoms to which they are attached form a γ-butyrolactone,δ-valerolactone or 2,2-dimethyl-1,3-dioxan-4,6-dione ring.

In still another embodiment of compounds of Formulae (I) and (III), R¹is

and R¹⁵ is selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl and substituted heteroaryl. Preferably, R¹⁵ is methyl, ethyl,propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl,benzyl, 4-hydroxybenzyl or 3-pyridyl.

In still another embodiment, of Formulae (I) and (III), R¹ is

where R³⁷ is hydrogen, alky, substituted alkyl, acyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, heterocycloalkyl,substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl;

Z is O, Nor S; and

Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

Preferably, Z and CH₂OC(O)— are in a conjugated relationship with oneanother (e.g. 1,4 or 1,2 related in a six membered ring system).

In still another embodiment, of Formulas (I) and (III), R¹ is

where q is 0 or 1;

R³⁸ and R³⁹ are independently hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted alkyl aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

R⁴⁰ and R⁴¹ are independently hydrogen, alkyl, substituted alkyl,cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; or together with the carbon atom to which theyare attached form a cycloalkyl ring

R⁴² and R⁴³ are independently alkyl, substituted alkyl, cycloalkyl,substituted alkyl, aryl, substituted aryl, heteroaryl and substitutedaryl or together with the carbon atoms to which they are attached forman aryl, substituted aryl, heteroaryl or substituted aryl ring; and

R³⁷ is as previously defined.

In a preferred embodiment of compounds of Formulae (I)-(IV), Y is O, R³,R⁶ and R⁷ are hydrogen and R⁴ and R⁵ together with the carbon atom towhich they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, bridged cycloalkyl orsubstituted bridged cycloalkyl ring. In another preferred embodiment ofcompounds of Formulae (I)-(IV), R⁴ and R⁵ together with the carbon atomto which they are attached form a cycloalkyl or substituted cycloalkylring. In one embodiment n is 0, t is 0 and u is 0. In anotherembodiment, n is 1 and R² is hydrogen, methyl, 2-propyl, 2-butyl,isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl,4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂SCH₃,CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In still anotherembodiment, n is 1 and R² and R¹⁶ together with the atoms to which theyare attached form a pyrrolidine ring.

In still another preferred embodiment of compounds of Formulae (I)-(IV),R⁴ and R⁵ together with the carbon atom to which they are attached forma cyclobutyl or substituted cyclobutyl ring. Preferably, the substitutedcyclobutyl ring is substituted with one or more substituents selectedfrom the group consisting of alkanyl, substituted alkanyl, halo,hydroxy, carboxyl and alkoxycarbonyl.

In still another preferred embodiment of compounds of Formulae (I)-(IV),R⁴ and R⁵ together with the carbon atom to which they are attached forma cyclopentyl or substituted cyclopentyl ring. Preferably, thecyclopentyl ring is substituted with alkanyl, substituted alkanyl, halo,hydroxy, carboxyl or alkoxycarbonyl. More preferably, the cyclopentylring is substituted with alkanyl. Even more preferably, the cyclopentylring is selected from the group consisting of

Preferably, in a more specific version of the above embodiments, R⁷ ishydrogen.

In still another preferred embodiment of compounds of Formulae (I)-(IV),R⁴ and R⁵ together with the carbon atom to which they are attached forma cyclohexyl or substituted cyclohexyl ring. Preferably, the cyclohexylring is substituted with alkanyl, substituted alkanyl, halo, hydroxy,carboxyl or alkoxycarbonyl. More preferably, the cyclohexyl ring issubstituted with alkanyl. Even more preferably, the cyclohexyl ring isselected from the group consisting of

Preferably, in a more specific version of the above embodiments, R⁷ ishydrogen.

In still another preferred embodiment of compounds of Formulae (I)-(IV),R⁴ and R⁵ together with the carbon atom to which they are attached forma cycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment, n is 0. In another embodiment, n is 1, and R² ishydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl,cyclohexyl, phenyl, benzyl, 4-

hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In still anotherembodiment, n is 1 and R² and R¹⁶ together with the atoms to which theyare attached form a pyrrolidine ring. Preferably, R⁴ and R⁵ togetherwith the carbon atom to which they are attached form acycloheteroalkanyl ring. More preferably, the cycloheteroalkanyl ring isselected from the group consisting of

wherein Z is O, S(O)_(p) or NR¹⁸;

p is 0, 1 or 2; and

R¹⁸ is selected from the group consisting of hydrogen, alkyl,substituted alkyl, acyl and alkoxycarbonyl. More preferably, thecycloheteroalkanyl ring is selected from the group consisting of

Preferably, in a more specific version of the above embodiments, R⁷ ishydrogen.

In still another embodiment of compounds of Formulae (I)-(IV), R⁴ and R⁵together with the carbon atom to which they are attached form a bridgedcycloalkyl ring. In one embodiment, n is 0. In another embodiment, n is1 and R² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl,cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl,2-imidazolyl, 2-indolyl, —CH₂OH, —CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H,—CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃, CH₂SH, —CH₂(CH₂)₃NH₂ or—CH₂CH₂CH₂NHC(NH)NH₂. In another embodiment, n is 1 and R² and R¹⁶together with the atoms to which they are attached form a pyrrolidinering. Preferably, the bridged cycloalkyl group is

Preferably, in a more specific version of the above embodiments, R⁷ ishydrogen.

In still another embodiment of compounds of Formulae (I)-(IV), Y is O,R⁶ and R⁷ are hydrogen, R⁴ is alkyl or cycloalkyl, R⁵ is hydrogen oralkyl and R³ is hydrogen or alkyl. In one embodiment, n is 0. In anotherembodiment, n is 1 and R² is hydrogen, methyl, 2-propyl, 2-butyl,isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl,4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. In still anotherembodiment, n is 1 and R² and R¹⁶ together with the atoms to which theyare attached form a pyrrolidine ring. Preferably, R⁴ is cycloalkyl, R⁵is hydrogen or methyl, and R³ is hydrogen or methyl. Preferably, R³ ishydrogen, R⁴ is isobutyl and R⁵ is hydrogen.

In still another embodiment of compounds of Formulae (I)-(IV), Y is O,R⁵ and R⁷ are hydrogen or alkanyl, R³ and R⁶ are hydrogen and R⁴ issubstituted heteroalkyl. Preferably, R⁴ is

A is NR¹⁹, O or S;

B is alkyl, substituted alkyl, alkoxy, halogen, hydroxy, carboxyl,alkoxycarbonyl or amino;

R¹⁹ is hydrogen, alkyl, cycloalkyl or aryl;

j is an integer from 0 to 4;

k is an integer from 1 to 4; and

l is an integer from 0 to 3.

More preferably, k is 1.

In still another embodiment of compounds of Formulae (I)-(IV), Y is O,R⁵ and R⁷ are hydrogen or alkanyl, R³ and R⁶ are hydrogen and R⁴ issubstituted alkanyl, cycloalkanyl or substituted cycloalkanyl.Preferably, R⁴ is selected from the group consisting of

Preferably, R⁴ is

h is an integer from 1 to 6; and

i is an integer from 0 to 6.

More preferably, h is 1, 2, 3 or 4 and i is 0 or 1. Even morepreferably, R⁴ is selected from the group consisting of

Preferably, compounds of Formulae (I)-(IV) are derived from a GABAanalog of Formula (XIII):

wherein the GABA analog of Formula (XIII) is selected from the groupconsisting of:

1-Aminomethyl-1-cyclohexane acetic acid;

1-Aminomethyl-1-(3-methylcyclohexane) acetic acid;

1-Aminomethyl-1-(4-methylcyclohexane) acetic acid;

1-Aminomethyl-1-(4-isopropylcyclohexane) acetic acid;

1-Aminomethyl-1-(4-tert-butylcyclohexane) acetic acid;

1-Aminomethyl-1-(3,3-dimethylcyclohexane) acetic acid;

1-Aminomethyl-1-(3,3,5,5-tetramethylcyclohexane) acetic acid;

1-Aminomethyl-1-cyclopentane acetic acid;

1-Aminomethyl-1-(3-methylcyclopentane) acetic acid;

1-Aminomethyl-1-(3,4-dimethylcyclopentane) acetic acid;

7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid;

9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid;

4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid;

3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid;

4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid;

3-Aminomethyl-3-(tetrahydrothiopyran-3-yl) acetic acid;

3-Aminomethyl-5-methyl-hexanoic acid;

3-Aminomethyl-5-methyl-heptanoic acid;

3-Aminomethyl-5-methyl-octanoic acid;

3-Aminomethyl-5-methyl-nonanoic acid;

3-Aminomethyl-5-methyl-decanoic acid;

3-Aminomethyl-5-cyclopropyl-hexanoic acid;

3-Aminomethyl-5-cyclobutyl-hexanoic acid;

3-Aminomethyl-5-cyclopentyl-hexanoic acid;

3-Aminomethyl-5-cyclohexyl-hexanoic acid;

3-Aminomethyl-5-phenyl-hexanoic acid;

3-Aminomethyl-5-phenyl-pentanoic acid;

3-Aminomethyl-4-cyclobutyl-butyric acid;

3-Aminomethyl-4-cyclopentyl-butyric acid;

3-Aminomethyl-4-cyclohexyl-butyric acid;

3-Aminomethyl-4-phenoxy-butyric acid;

3-Aminomethyl-5-phenoxy-hexanoic acid; and

3-Aminomethyl-5-benzylsulfanyl-pentanoic acid.

Particularly preferred embodiments of Formula (I) include compounds ofFormulae (V) and (VI):

where R¹, R², R⁷ and R¹⁶ are as previously defined.

In one embodiment of compounds of Formulae (V) and (VI), n is 0. Inanother embodiment, n is 1 and R² is hydrogen, methyl, 2-propyl,2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl,4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. Preferably, in the aboveembodiments, R⁷ is hydrogen.

In another embodiment of compounds of Formulae (V) and (VI), n is 1, R¹is R²⁴C(O)— or R²⁴C(S)—; and R²⁴ is alkyl, substituted alkyl,heteroalkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl. Preferably, R²⁴ is methyl, ethyl, 2-propyl, t-butyl,—CH₂OCH(CH₃)₂, phenyl or 3-pyridyl. Preferably, in this embodiment, R⁷is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl,aryl or substituted aryl. More preferably, R⁷ is hydrogen, methyl,ethyl, benzyl, —C(CH₃)═CH₂, —CH₂C(O)N(CH₃)₂,

where V is O or CH₂.

Most preferably, R⁷ is hydrogen.

In still another embodiment of compounds of Formulae (V) and (VI), n is1, R¹ is R²⁵OC(O)— or R²⁵SC(O)—; and R²⁵ is alkyl, substituted alkyl,heteroalkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl. Preferably, R²⁵ is ethyl, 2-propyl, neopentyl,—CH₂OCH(CH₃)₂, phenyl or 2-pyridyl. Preferably in this embodiment, R⁷ ishydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl,aryl or substituted aryl. More preferably, R⁷ is hydrogen, methyl,ethyl, benzyl, —C(CH₃)═CH₂, —CH₂C(O)N(CH₃)₂,

where V is O or CH₂.

Most preferably, R⁷ is hydrogen.

In still another embodiment of compounds of Formulae (V) and (VI), R¹ is

and R¹⁵ is selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl and substituted heteroaryl. Preferably, R¹⁵ is methyl, ethyl,propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl,benzyl, 4-hydroxybenzyl or 3-pyridyl. In a more specific version of thisembodiment, R⁷ is hydrogen, alkanyl, substituted alkanyl, alkenyl,substituted alkenyl, aryl or substituted aryl. More preferably, R⁷ ishydrogen, methyl, ethyl, benzyl, —C(CH₃)═CH₂, —CH₂C(O)N(CH₃)₂,

where V is O or CH₂.

Preferably, R⁷ is hydrogen.

Particularly preferred embodiments of compounds of Formulae (V) and (VI)are compounds selected from the group consisting of:

1-{[((5-methyl-2-oxo-1,3-dioxol-4-en-4-yl)methoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid; and

3-{[((5-methyl-2-oxo-1,3-dioxol-4-en-4-yl)methoxy)carbonyl]aminomethyl}-5-methyl-hexanoicacid.

In still another embodiment of compounds of Formulae (V) and (VI), R¹ is

m is 0, and R⁸, R¹¹ and R¹² are as previously defined. In one embodimentof compounds of Formulae (V) and (VI), R¹¹ is acyl, alkoxycarbonyl,aryloxycarbonyl, cycloalkoxycarbonyl, carbamoyl or substitutedcarbamoyl, R⁸ is hydrogen, alkoxycarbonyl, alkyl, aryl, arylalkyl orcyano and R¹² is hydrogen, alkoxycarbonyl, alkyl, substituted alkyl,aryl, or arylalkyl. In another embodiment of compounds of Formulae (V)and (VI), R¹¹ is selected from the group consisting of acetyl,propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl,cyclohexanecarbonyl, benzoyl, phenacetyl, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl,benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl,N-isobutylcarbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl,N-cyclopentylcarbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl,N-benzylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N,N-dipropylcarbamoyl, N,N-diisopropylcarbamoyl, N,N-dibutylcarbamoyl,N,N-dibenzylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyland N-morpholinylcarbamoyl. In still another embodiment of compounds ofFormulae (V) and (VI), R¹¹ is selected from the group consisting ofacetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl,phenacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl,phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl,N-phenylcarbamoyl, N-benzylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N-pyrrolidinylcarbamoyl,N-piperidinylcarbamoyl and N-morpholinylcarbamoyl.

In one embodiment of compounds of Formulae (V) and (VI), R⁸ is selectedfrom the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl,phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyland cyano. Preferably, R⁸ is selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl,ethoxycarbonyl and butoxycarbonyl.

In still another embodiment of compounds of Formulae (V) and (VI), R¹²is selected from the group consisting of hydrogen, methyl, ethyl,propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl andbenzyloxycarbonyl. Preferably R¹² is selected from the group consistingof hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl,ethoxycarbonyl and butoxycarbonyl.

In still another embodiment of compounds of Formulae (V) and (VI), R¹¹is selected from the group consisting of hydrogen, alkoxycarbonyl,alkyl, substituted alkyl, aryl, arylalkyl and R⁸ and R¹² together withthe carbon atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring. Preferably, R¹¹ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl,ethoxycarbonyl and butoxycarbonyl, and R⁸ and R¹² together with thecarbon atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Morepreferably, R¹¹ is hydrogen or methyl and R⁸ and R¹² together with thecarbon atoms to which they are attached form a 2-cyclopenten-1-one,2-cyclohexen-1-one, 2-(5H)-furanone or 5,6-dihydro-pyran-2-one ring.

In still another embodiment of compounds of Formulae (V) and (VI), R¹²is selected from the group consisting of hydrogen, alkoxycarbonyl,alkyl, substituted alkyl, aryl, arylalkyl and R⁸ and R¹¹ together withthe carbon atoms to which they are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring. Preferably, R¹² is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl,ethoxycarbonyl and butoxycarbonyl, and R⁸ and R¹¹ together with thecarbon atoms to which they are attached form a cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Morepreferably, R¹² is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl,ethoxycarbonyl and butoxycarbonyl, and R⁸ and R¹¹ together with thecarbon atoms to which they are attached form a γ-butyrolactone,δ-valerolactone or 2,2-dimethyl-1,3-dioxan-4,6-dione ring.

In a more specific version of the above embodiments of compounds ofFormulae (V) and (VI), R⁷ is hydrogen, alkanyl, substituted alkanyl,alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably,R⁷ is hydrogen, methyl, ethyl, benzyl, —C(CH₃)═CH₂, —CH₂C(O)N(CH₃)₂,

where V is O or CH₂.

Most preferably R⁷ is hydrogen.

Particularly preferred embodiments of compounds of Formulae (V) and (VI)are compounds selected from the group consisting of:

Piperidinium 1-{(1-methyl-3-oxo-but-1-enyl)aminomethyl}-1-cyclohexaneacetate;

Piperidinium1-{1-[(2-oxo-tetrahydrofuran-3-ylidene)ethyl]aminomethyl}-1-cyclohexaneacetate;

Piperidinium1-{(2-carbomethoxy-cyclopent-1-enyl)aminomethyl}-1-cyclohexane acetate;and

Piperidinium1-{(1-methyl-2-(ethoxycarbonyl)-3-ethoxy-3-oxoprop-1-enyl)aminomethyl}-1-cyclohexaneacetate.

In a particularly preferred embodiment, compounds of Formula (IV) havethe structure of Formulae (VII) or (VIII):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein:

n, R², R⁷, R¹³, R¹⁴, R¹⁶ and R²⁵ are as previously defined.

In one preferred embodiment, the compounds of Formulae (VII) and (VIII)do not include the following compounds:

if either R¹³ or R¹⁴ is hydrogen, alkoxycarbonyl, substitutedalkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substitutedcycloalkoxycarbonyl, then the other of R¹³ or R¹⁴ is not hydrogen; and

R²⁵C(O) is not a moiety derived from a bile acid.

In one embodiment of compounds of Formulae (VII) and (VIII), n is 0. Inanother embodiment, n is 1. When n is 1, preferably the α-amino acid isof the L-stereochemical configuration.

In another embodiment of compounds of Formulae (VII) and (VIII), R⁷ ishydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl,aryl or substituted aryl. Preferably, R⁷ is hydrogen, methyl, ethyl,benzyl, —C(CH₃)═CH₂, —CH₂C(O)N(CH₃)₂,

where V is O or CH₂.

Most preferably, R⁷ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII), nis 0. In still another embodiment of compounds of Formulae (VII) and(VIII), n is 1, R¹⁶ is hydrogen and R² is hydrogen, methyl, 2-propyl,2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl,4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂. Preferably R¹⁶ ishydrogen and R² is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl,tert-butyl, cyclohexyl, phenyl or benzyl. In still another embodiment, nis 1 and R² and R¹⁶ together with the atoms to which they are attachedform a pyrrolidine ring.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ismethyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isethyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ispropyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isisopropyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isbutyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isisobutyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ issec-butyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ istert-butyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ iscyclopentyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ iscyclohexyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ismethyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ismethoxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isethoxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ ispropoxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isisopropoxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isbutoxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isisobutoxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ issec-butoxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenetbyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ istert-butoxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ iscyclohexyloxycarbonyl and R¹⁴ is methyl.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isphenyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isbenzyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ isphenethyl and R¹⁴ is hydrogen.

In still another embodiment of compounds of Formulae (VII) and (VIII),R²⁵ is selected from the group consisting of methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl,I,l-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl,1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl,1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl,1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl,1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl,1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl,1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl,phenacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R¹³ is3-pyridyl and R¹⁴ is hydrogen.

Particularly preferred embodiments of compounds of Formulae (VII) and(VIII) include compounds selected from the group consisting of:

1-{[(α-Acetoxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;

1-{[(α-Propanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Butanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Pivaloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;

1-{[(α-Benzoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;

1-{[(α-Acetoxybutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;

1-{[(α-Butanoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Isobutanoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Benzoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;

1-{[(α-Acetoxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;

1-{[(α-Propanoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Butanoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-Pivaloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-2,2-Diethoxypropanoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;

1-{[(α-2-(1,3-Dioxolan-2-yl)propanoyldxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-(2-Amino-2-methylpropanoyl)oxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Nicotinoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Acetoxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Butanoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Isobutanoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-Benzoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(α-Acetoxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid;

1-{[(α-Benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid;

1-{[(1-(3-Methylbutanoyloxy)-2-phenylethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(1-Benzoyloxy-2-phenylethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[N-[(α-Isobutanoyloxyethoxy)carbonyl]-4-bromophenylalaninyl]-aminomethyl}-1-cyclohexaneacetic acid;

3-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methylhexanoic acid;

3-{[(α-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-5-methylhexanoicacid; and

3-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-5-methylhexanoic acid.

In one embodiment, the compounds of the invention have the structure ofFormula (II):

In an embodiment of compounds of Formula (II), when R³, R⁵ and R⁶ arehydrogen, R⁴ is not phenyl or substituted phenyl. More preferably, R⁴ isnot 4-chlorophenyl.

In a preferred embodiment, the compounds of Formula (II) have thestructure of Formulae (IX) and (X):

In one embodiment of compounds of Formulae (IX) and (X), t is 0. Inanother embodiment, t is 1 and R² is hydrogen, methyl, 2-propyl,2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl,4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, —CH₂OH,—CH(OH)CH₃, —CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CONH₂, —CH₂CH₂CONH₂, —CH₂CH₂SCH₃,—CH₂SH, —CH₂(CH₂)₃NH₂ or —CH₂CH₂CH₂NHC(NH)NH₂.

In still another embodiment of compounds of Formulae (IX) or (X), R²⁰and R²¹ are independently selected from the group consisting of alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl and substitutedheteroaryl. Preferably, R²⁰ and R²¹ are independently selected from thegroup consisting of alkyl, substituted aryl and heteroaryl. In oneembodiment, R²⁰ is methyl and R²¹ is methyl. Preferably, in this lastembodiment, R⁷ is hydrogen, methyl, ethyl, benzyl, —C(CH₃)═CH₂,—CH₂C(O)N(CH₃)₂,

where V is O or CH₂.

Most preferably, R⁷ is hydrogen.

In another embodiment of compounds of Formulae (IX) or (X), R²⁰ and R²¹together with the carbon atom to which they are attached form acycloalkyl or substituted cycloalkyl ring. In one embodiment, R²⁰ andR²¹ together with the carbon atom to which they are attached form acyclohexyl ring. Preferably, in this last embodiment, R⁷ is hydrogen,methyl, ethyl, benzyl, —C(CH₃)═CH₂, —CH₂C(O)N(CH₃)₂,

where V is O or CH₂.

Most preferably, R⁷ is hydrogen.

In one embodiment, the compounds of the invention have the structure ofFormula (III):

In one embodiment of the compounds of Formula (III), n is 1, R¹ ishydrogen and R² is arylalkyl. Preferably, R² is benzyl. In anotherembodiment of the compounds of Formula (III), n is 0 and R¹ isR²⁵OC(O)—. Preferably, R²⁵ is alkyl or substituted alkyl. Morepreferably, R²⁵ is ethyl. In still another embodiment of the compoundsof Formula (III), R²² and R²³ are hydrogen. In still another embodiment,R²² and R²³ are alkyl or substituted alkyl. Preferably, R²² and R²³ aremethyl.

In a preferred embodiment, the compounds of Formula (III) have thestructure of Formula (XI):

In one embodiment of the compounds of Formula (XI), n is 1, X is NH, Yis O, R¹ is hydrogen, R² is benzyl, R²² is methyl and R²³ are methyl. Inanother embodiment, n is 0, Y is O, R¹ is R²⁵OC(O)—, R²⁵ is ethyl, R²²is hydrogen and R²³ is hydrogen.

In another embodiment, the compounds of Formula (III) have the structureof Formula (XII):

In one embodiment of the compounds of Formula (XII), n is 1, X is NH, Yis O, R¹ is hydrogen, R² is benzyl, R²² is methyl and R²³ are methyl. Inanother embodiment, n is 0, Y is O, R¹ is R²⁵OC(O)—, R²⁵ is ethyl, R²²is hydrogen and R²³ is hydrogen.

The instant invention also comprises a GABA analog derivative, M-G, foradministration to a patient in need of therapy, wherein M is a promoietyand G is derived from a GABA analog, H-G (where H is hydrogen). Thepromoiety M, once cleaved from G, and any metabolite thereof, exhibits acarcinogenically toxic dose (TD₅₀) in rats of greater than 0.2mmol/kg/day. Further, the promoiety M is cleaved from G at a sufficientrate in vivo, upon colonic administration to rats, to produce:

-   -   (i) a maximum concentration of H-G in plasma (C_(max)) of at        least 120% of the C_(max) of H-G in plasma achieved by        colonically administering an equimolar dose of H-G; and    -   (ii) an AUC that is at least 120% of the AUC achieved by        colonically administering an equimolar dose of H-G.

Preferably, M-G has the structure of Formula (XIV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,wherein:

M is a promoiety;

Y is O or S;

R is hydrogen, or R and R⁶ together with the atoms to which they areattached form an azetidine, substituted azetidine, pyrrolidine orsubstituted pyrrolidine ring;

R³ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

R⁴ and R⁵ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl or optionally, R⁴ and R⁵ together with the carbon atomto which they are attached form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkylring; and

R⁷ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.

In a preferred embodiment, M has the structure of Formula (XV):

wherein:

n, X, R¹ and R² are as previously defined

In one embodiment, M-G include compounds wherein H-G, once cleaved fromM, is substantially free of any lactam having the structure of Formula(XVI):

wherein R is hydrogen and R³, R⁴, R⁵ and R⁶ are as previously defined

Preferably, promoiety M or any metabolite formed from M does not formformaldehyde or pivalic acid upon cleavage of G-M. In one embodiment,the promoiety M is cleaved from G at a sufficient rate in vivo, uponcolonic administration to rats, to produce a C_(max) of H-G in plasma ofat least 200%, and most preferably at least 1000%, of the C_(max) of H-Gin plasma achieved by colonically administering an equimolar dose ofH-G. Preferably, the promoiety M is cleaved from G at a sufficient ratein vivo, upon colonic administration to rats, to produce an AUC of H-Gin plasma of at least 200%, and most preferably at least 500%, of theAUC of H-G in plasma achieved by colonically administering an equimolardose of H-G. In another embodiment, the promoiety M is cleaved from H-Gat a sufficient rate in vivo, following oral administration to dogs(e.g., using an osmotic mini-pump device) at a dose of about 60 μmolequivalent of H-G per kg, to produce a plasma concentration of H-G at 12hours post dosing of at least 200% of the plasma concentration of H-Gachieved from an equimolar dose of H-G following the same mode ofadministration.

4.3 Synthesis of the Compounds of the Invention

The compounds of the invention may be obtained via the synthetic methodsillustrated in Schemes 1-17. Those of skill in the art will appreciatethat a preferred synthetic route to the compounds of the inventionconsists of attaching promoieties to GABA analogs. Numerous methods havebeen described in the art for the synthesis of GABA analogs (See, e.g.,Satzinger et al., U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat.No. 5,563,175; Horwell et al., U.S. Pat. No. 6,020,370; Silverman etal., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932;Silverman et al., U.S. Pat. No. 6,117,906; Silverman, InternationalPublication No. WO 92/09560; Silverman et al., International PublicationNo. WO 93/23383; Horwell et al., International Publication No. WO97/29101, Horwell et al., International Publication No. WO 97/33858;Horwell et al., International Publication No. WO 97/33859; Bryans etal., International Publication No. WO 98/17627; Guglietta et al.,International Publication No. WO 99/08671; Bryans et al., InternationalPublication No. WO 99/21824; Bryans et al., International PublicationNo. WO 99/31057; Belliotti et al., International Publication No. WO99/31074; Bryans et al., International Publication No. WO 99/31075;Bryans et al., International Publication No. WO 99/61424; Bryans et al.,International Publication No. WO 00/15611; Bryans, InternationalPublication No. WO 00/31020; and Bryans et al., InternationalPublication No. WO 00/50027). Other methods are known in the art forsynthesizing GABA analogs, which are readily accessible to the skilledartisan. The promoieties described herein, are known in the art and maybe prepared and attached to GABA analogs by established procedures (Seee.g., Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991); Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996); “BeilsteinHandbook of Organic Chemistry,” Beilstein Institute of OrganicChemistry, Frankfurt, Germany; Feiser et al., “Reagents for OrganicSynthesis,” Volumes 1-17, Wiley Interscience; Trost et al.,“Comprehensive Organic Synthesis,” Pergamon Press, 1991; “Theilheimer'sSynthetic Methods of Organic Chemistry,” Volumes 1-45, Karger, 1991;March, “Advanced Organic Chemistry,” Wiley Interscience, 1991; Larock“Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette,“Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons,1995, Bodanzsky, “Principles of Peptide Synthesis,” Springer Verlag,1984; Bodanzsky, “Practice of Peptide Synthesis,” Springer Verlag,1984).

Accordingly, starting materials useful for preparing compounds of theinvention and intermediates thereof are commercially available or can beprepared by well-known synthetic methods. Other methods for synthesis ofthe prodrugs described herein are either described in the art or will bereadily apparent to the skilled artisan in view of the referencesprovided above and may be used to synthesize the compounds of theinvention. Accordingly, the methods presented in the Schemes herein areillustrative rather than comprehensive.

In any of the Schemes below, after the amino group of a GABA analog hasbeen functionalized with a promoiety or other protecting group, thecarboxylic acid group may be converted to an ester or thioester by manysynthetic methods, which are well-known to the skilled artisan. In onepreferred embodiment, GABA analogs may be reacted with an alcohol orthiol in the presence of a coupling reagent (e.g., carbodiimide anddimethylaminopyridine) to provide the ester. In another preferredembodiment, GABA analogs may be reacted with an alkyl halide in thepresence of base to yield the ester. Other methods for converting GABAanalogs to esters or thioesters are well within the purview of theskilled artisan in view of the references provided herein.

As illustrated above in Scheme 1, carboxylic acids can be directlycoupled to the terminal amino (or hydroxyl) group of GABA analogderivatives (6) to provide adducts (7). Reagents for effecting thisreaction are well known to the skilled artisan and include, but are notlimited to, carbodiimides, aminium salts, phosphonium salts, etc.Alternatively, reaction of carboxylic acid derivatives such as acylchlorides, symmetrical anhydrides or mixed anhydrides with GABA analogs(6) in the presence of base (e.g., hydroxide, tertiary amines, etc.) maybe used to synthesize (7).

As illustrated in Scheme 2, GABA analog derivatives (6) may be convertedto carbamates (8) by treatment with various carbonic acid derivatives inthe presence of base (e.g., hydroxide, tertiary amines, etc.).Alternatively, the well-known addition of alcohols to isocyanates (9) or(10) may be used to synthesize (8).

As illustrated in Scheme 3, GABA analog derivatives (6) may be convertedto thioamides (11) by reaction with thioacids in the presence ofcoupling agents. Reagents for effecting this reaction are well known tothe skilled artisan and include, but are not limited to, carbodiimides,aminium salts, phosphonium salts, etc. Alternatively, reaction of thioacid derivatives such as thioacyl chlorides, symmetrical anhydrides ormixed anhydrides with (6) in the presence of base (e.g., hydroxide,tertiary amines, etc.) may be used to synthesize thioamides (11). In yetanother method, amides (7) may be converted to thioamides (11) byheating in the presence of phosphorus pentasulfide (when n=0).

Thiocarbamates (12) and (13) may be synthesized from the reaction of thecorresponding thiocarbonate derivatives (i.e., P=O, Q=S and P=S Q=O,respectively) where W is chloride, imidazolyl or 4-nitrophenoxy withGABA analog derivatives (6) in the presence of base. Thiocarbamate (13)may also be formed by reaction of a thiol with isocyanates (9) or (10).Dithiocarbamate (14) (P=S, Q=S) may be made by reaction of GABA analogderivatives (6) with the dithiocarbonate derivative (i.e., P and Q=S)where W is chloride, imidazolyl or 4-nitrophenoxy in the presence ofbase (see Scheme 4).

One method for synthesis of compounds of Formula (IV) is illustrated inScheme 5.

Chloroformate (15) is treated with an aromatic leaving group such asp-nitrophenol in the presence of base to provide p-nitrophenylcarbonate(16). Halide interchange provides iodide (17), which is reacted with ametal or tetraalkylammonium salt of a carboxylic acid to afford compound(18). Treatment of (18) with GABA analog derivative (19), optionally inthe presence of trimethylsilyl chloride, affords a compound of Formula(IV). Methods for making related acyloxyalkyl carbamate compounds havebeen described in the art (Alexander, U.S. Pat. No. 4,760,057;Alexander, U.S. Pat. No. 4,916,230; Alexander, U.S. Pat. No. 5,466,811;Alexander, U.S. Pat. No. 5,684,018).

Alternatively compounds of Formula (IV) can be prepared from carbonate(18) in a stepwise fashion as illustrated in Scheme 6. Here reaction of(18) with an α-amino acid (20), optionally protected as an ester,affords intermediate (21) which upon deprotection (if necessary)provides compound (22), which is then coupled to GABA analog (23) usingstandard peptide coupling reagents well known in the art.

Another method for synthesis of compounds of Formula (IV) proceeds viacarbonylation of GABA analog derivative (19) to an intermediate carbamicacid species, which is captured by an in situ alkylation reaction in anadaptation of the methods disclosed in the art (Butcher, Synlett, 1994,825-6; Ferres et al., U.S. Pat. No. 4,036,829). Carbon dioxide gas isbubbled into a solution containing (19) and a base (e.g., Cs₂CO₃, Ag₂CO₃or AgO) in a solvent such as DMF or NMP. The activated halide is added,optionally in the presence of iodide ion as a catalyst, and thecarbonylation continued until the reaction is completed. This method isillustrated in Scheme 7 for the preparation of compounds of Formula (IV)from halide (24).

Alternatively compounds of Formula (IV) can be prepared in a stepwisefashion as illustrated in Scheme 8. Carbonylation and alkylation ofcarboxyl protected α-amino acid (20) provides intermediate (21), whichupon deprotection is coupled to GABA analog (23) as previously describedin Scheme 6.

Yet another method for synthesis of compounds of Formula (IV) reliesupon oxidation of ketocarbamate derivatives of GABA analogs (Gallop etal., co-pending U.S. patent application Ser. No. Ser. No. 10/167,797entitled “Methods for Synthesis of Prodrugs from 1-Acyl-AlkylDerivatives and Compositions Thereof”). As illustrated in Scheme 9,oxidation of ketocarbamate (25) affords compounds of Formula (IV).Preferred solvents include, but are not limited to, t-butanol,diethylether, acetic acid, hexane, dichloroethane, dichloromethane,ethyl acetate, acetonitrile, methanol, chloroform and water. Generally,the oxidant may be an organism (e.g., yeast or bacteria), or a chemicalreagent (e.g., an enzyme or peroxide). Preferred oxidants include those,which have been successfully used in Baeyer-Villager oxidations ofketones to esters or lactones (Strukul, Angnew. Chem. Int. Ed., 1998,37, 1198; Renz et al., Eur. J. Org. Chem. 1999, 737; Beller et al., in“Transition Metals in Organic Synthesis” Chapter 2, Wiley VCH; Stewart,Current Organic Chemistry, 1998, 2, 195; Kayser et al., Synlett, 1999,1, 153).

Other compounds of this invention may be amenable to synthesis from theappropriate ketocarbamate derivative via this Baeyer-Villiger typeoxidation, provided that they do not contain chemical functionalitysusceptible to decomposition or other transformation under conditions ofthe reaction.

Ketocarbamates (25) may be prepared from the correspondingα-hydroxyketone compounds (26) either directly, via reaction withisocyanate (9), or by first converting the α-hydroxyketone compound to ahaloformate or activated carbonate intermediate (27) and subsequentlyreacting with compound (19), as illustrated in Scheme 10.

Alternatively ketocarbamate (25) can be prepared in a stepwise mannervia the α-amino acid carbamate (28) as illustrated in Scheme 11,following the coupling methodologies described above.

Note that one method for preparation of isocyanate derivatives of GABAanalogs (i.e., compounds (9)) used in Scheme 10 above begins with theappropriate six-membered anhydride (29) as illustrated in Scheme 12. Theanhydride ring is opened by reaction with an alcohol or thiolnucleophile to afford carboxylic acid (30). This compound is convertedto the intermediate acyl azide in either a 2-step sequence (i.e., firstactivation of the carboxyl group as a mixed anhydride, acyl halide orsynthetic equivalent and then displacement with azide) or directly(e.g., by treatment with Ph₂P(O)N₃). Curtius rearrangement of the acylazide intermediate by thermolysis in an appropriate solvent (e.g.,toluene) at a temperature between 0° C. to 120° C. affords isocyanate(9). Optionally, the isocyanate is not isolated but rather is generatedin situ and quenched by reaction with α-hydroxyketone (26) to afford thedesired product (25).

One method for synthesis of oxodioxolenylmethyl carbamate prodrugs (36)is disclosed in Scheme 13. Hydroxyketone (31) is treated with phosgeneor carbonyldiimidazole in the presence of base to yield cyclic carbonate(32). Free radical bromination with N-bromosuccinimide andazoisobutryonitrile provides bromide (33), which is converted to alcohol(34). Alcohol (34) is transformed to dicarbonate (35) by reaction with4-nitrophenyl chloroformate, which is then reacted with GABA analogderivatives (19) to provide prodrugs (36). Alternatively, reaction ofcompound (34) with isocyanate (9) provides compound (36), where n is 0.

Prodrugs (41) may be synthesized by the method disclosed in Scheme 14.Carboxylic acid (37) is coupled to alcohol (38) (e.g.,dicylohexylcarbodiimide and pyridine) to provide ester (39). Ester (39)is converted to activated carbonate (40) by reaction with 4-nitrophenylchloroformate, which is then reacted with GABA analog derivative (19) toprovide prodrug (41).

Enamine prodrugs such as (43) may be synthesized simply by reactingactivated carbonyl compounds (42) with GABA analog derivatives (19)(where R¹⁶═H), optionally in the presence of a secondary amine ascatalyst, under dehydrating conditions as shown in Scheme 15.

Compounds (III) may be synthesized by the route illustrated in Scheme16. Reaction of GABA analog (23) with an α-activated ester derivative(44) provides amino ester (45). The amino group of (45) is blocked byacylation to yield (46) (e.g., using the methods described above) andthe free acid is esterified under standard conditions to yield thediester (47). Dieckman condensation followed by decarboxylation yieldsketone (48). Peroxy acid oxidation then provides lactone (III).

Imine prodrugs (II) may be synthesized as depicted in Scheme 17 bytreating ketones or ketone equivalents (49) with GABA analog derivatives(50) under dehydrating conditions.

Phosphorus prodrugs may be synthesized by conventional methods known inthe art. Similarly, prodrugs with S—N bond may be synthesized by usingprocedures described in the art.

4.4 Therapeutic Uses of the Compounds of the Invention

In accordance with the invention, a compound and/or composition of theinvention is administered to a patient, preferably a human, sufferingfrom epilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially, neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders or ethanol withdrawal syndrome. Further, in certainembodiments, the compounds and/or compositions of the invention areadministered to a patient, preferably a human, as a preventative measureagainst various diseases or disorders. Thus, the compounds and/orcompositions of the invention may be administered as a preventativemeasure to a patient having a predisposition for epilepsy, depression,anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, pain (especially, neuropathic painand muscular and skeletal pain), inflammatory disease (i.e., arthritis),insomnia, gastrointestinal disorders and ethanol withdrawal syndrome.Accordingly, the compounds and/or compositions of the invention may beused for the prevention of one disease or disorder and concurrentlytreating another (e.g., prevention of psychosis while treatinggastrointestinal disorders; prevention of neuropathic pain whiletreating ethanol withdrawal syndrome).

The suitability of the compounds and/or compositions of the invention intreating epilepsy, depression, anxiety, psychosis, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain(especially neuropathic pain and muscular and skeletal pain),inflammatory disease (i.e., arthritis), insomnia, gastrointestinaldisorders and ethanol withdrawal syndrome may be determined by methodsdescribed in the art (See, e.g., Satzinger et al., U.S. Pat. No.4,024,175; Satzinger et al., U.S. Pat. No. 4,087,544; Woodruff, U.S.Pat. No. 5,084,169; Silverman et al., U.S. Pat. No. 5,563,175; Singh,U.S. Pat. No. 6,001,876; Horwell et al., U.S. Pat. No. 6,020,370;Silverman et al., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No.6,103,932; Silverman et al., U.S. Pat. No. 6,117,906; Silverman,International Publication No. WO 92/09560; Silverman et al.,International Publication No. WO 93/23383; Horwell et al., InternationalPublication No. WO 97/29101, Horwell et al., International PublicationNo. WO 97/33858; Horwell et al., International Publication No. WO97/33859; Bryans et al., International Publication No. WO 98/17627;Guglietta et al., International Publication No. WO 99/08671; Bryans etal., International Publication No. WO 99/21824; Bryans et al.,International Publication No. WO 99/31057; Magnus-Miller et al.,International Publication No. WO 99/37296; Bryans et al., InternationalPublication No. WO 99/31075; Bryans et al., International PublicationNo. WO 99/61424; Pande, International Publication No. WO 00/23067;Bryans, International Publication No. WO 00/31020; Bryans et al.,International Publication No. WO 00/50027; and Bryans et al.,International Publication No. WO 02/00209). The compounds and/orcompositions of the invention may be used to treat or prevent epilepsy,depression, anxiety, psychosis, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, panic, pain (especiallyneuropathic pain and muscular and skeletal pain), inflammatory disease(i.e., arthritis), insomnia, gastrointestinal disorders and ethanolwithdrawal syndrome by procedures described in the art (see referencesabove). Thus, it is well with the capability of those of skill in theart to assay and use the compounds and/or compositions of the inventionto treat or prevent epilepsy, depression, anxiety, psychosis, faintnessattacks, hypokinesia, cranial disorders, neurodegenerative disorders,panic, pain (especially, neuropathic pain and muscular and skeletalpain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders and ethanol withdrawal syndrome.

4.5 Therapeutic/Prophylactic Administration

The compounds and/or compositions of the invention may be advantageouslyused in human medicine. As previously described in Section 4.4 above,compounds and/or compositions of the invention are useful for thetreatment or prevention of epilepsy, depression, anxiety, psychosis,faintness attacks, hypokinesia, cranial disorders, neurodegenerativedisorders, panic, pain (especially, neuropathic pain and muscular andskeletal pain), inflammatory disease (i.e., arthritis), insomnia,gastrointestinal disorders or ethanol withdrawal syndrome.

When used to treat or prevent the above disease or disorders compoundsand/or compositions of the invention may be administered or appliedsingly, in combination with other agents. The compounds and/orcompositions of the invention may also be administered or appliedsingly, in combination with other pharmaceutically active agents,including other compounds of the invention.

The current invention provides methods of treatment and prophylaxis byadministration to a patient of a therapeutically effective amount of acomposition or compound of the invention. The patient may be an animal,is more preferably a mammal, and most preferably a human.

The present compounds and/or compositions of the invention, whichcomprise one or more compounds of the invention, are preferablyadministered orally. The compounds and/or compositions of the inventionmay also be administered by any other convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa,etc.). Administration can be systemic or local. Various delivery systemsare known, (e.g., encapsulation in liposomes, microparticles,microcapsules, capsules, etc.) that can be used to administer a compoundand/or composition of the invention. Methods of administration include,but are not limited to, intradermal, intramuscular, intraperitoneal,intravenous, subcutaneous, intranasal, epidural, oral, sublingual,intranasal, intracerebral, intravaginal, transdermal, rectally, byinhalation, or topically, particularly to the ears, nose, eyes, or skin.

In particularly preferred embodiments, the compounds and/or compositionsof the invention can be delivered via sustained release systems,preferably oral sustained release systems. In one embodiment, a pump maybe used (see Langer, supra; Sefton, 1987, CRC Crit Ref Biomed Eng.14:201; Saudek et al., 1989, N. Engl. J. Med. 321:574).

In another embodiment, polymeric materials can be used (see “MedicalApplications of Controlled Release,” Langer and Wise (eds.), CRC Pres.,Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; seealso Levy et al., 1985, Science 228: 190; During et al., 1989, Ann.Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105). In apreferred embodiment, polymeric materials are used for oral sustainedrelease delivery. Preferred polymers include sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferred,hydroxypropylmethylcellulose). Other preferred cellulose ethers havebeen described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3)1-9). Factors affecting drug release are well known to the skilledartisan and have been described in the art (Bamba et al., Int. J.Pharm., 1979, 2, 307).

In another embodiment, enteric-coated preparations can be used for oralsustained release administration. Preferred coating materials includepolymers with a pH-dependent solubility (i.e., pH-controlled release),polymers with a slow or pH-dependent rate of swelling, dissolution orerosion (i.e., time-controlled release), polymers that are degraded byenzymes (i.e., enzyme-controlled release) and polymers that form firmlayers that are destroyed by an increase in pressure (i.e.,pressure-controlled release).

In still another embodiment, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,2000, 26:695-708). In a preferred embodiment, OROS™ osmotic devices areused for oral sustained release delivery devices (Theeuwes et al., U.S.Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899).

In yet another embodiment, a controlled-release system can be placed inproximity of the target of the compounds and/or composition of theinvention, thus requiring only a fraction of the systemic dose (see,e.g., Goodson, in “Medical Applications of Controlled Release,” supra,vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussedin Langer, 1990, Science 249:1527-1533 may also be used.

The compounds and/or compositions of the invention preferably provideGABA analogs (e.g., gabapentin and pregablin) upon in vivoadministration to a patient. While not wishing to bound by theory, thepromoiety or promoieties of the compounds and/or compositions of theinvention may be cleaved either chemically and/or enzymatically. One ormore enzymes present in the stomach, intestinal lumen, intestinaltissue, blood, liver, brain or any other suitable tissue of a mammal mayenzymatically cleave the promoiety or promoieties of the compoundsand/or compositions of the invention. The mechanism of cleavage is notimportant to the current invention. Preferably, GABA analogs formed bycleavage of prodrugs from the compounds of the invention do not containsubstantial quantities of lactam contaminant (preferably, less than 0.5%by weight, more preferably, less than 0.2% by weight, most preferablyless than 0.1% by weight). The extent of release of lactam contaminantfrom the prodrugs of this invention may be assessed using the standardin vitro analytical methods.

While not wishing to bound by theory, the promoiety or promoieties ofthe compounds and/or compositions of the invention may be cleaved priorto absorption by the gastrointestinal tract (e.g., within the stomach orintestinal lumen) and/or after absorption by the gastrointestinal tract(e.g., in intestinal tissue, blood, liver or other suitable tissue of amammal). If the promoiety or promoieties of the compounds of theinvention are cleaved prior to absorption by the gastrointestinal tract,the resulting GABA analogs may be absorbed into the systemic circulationconventionally (e.g. via the large neutral amino acid transporterlocated in the small intestine). If the promoiety or promoieties of thecompounds of the invention are cleaved after absorption by thegastrointestinal tract, these GABA analog prodrugs may have theopportunity to be absorbed into the systemic circulation either bypassive diffusion, active transport or by both passive and activeprocesses.

If the promoiety or promoieties of the compounds of the invention arecleaved after absorption by the gastrointestinal tract, these GABAanalog prodrugs may have the opportunity to be absorbed into thesystemic circulation from the large intestine. In this situation, thecompounds and/or compositions of the invention are preferablyadministered as sustained release systems. In a preferred embodiment,the compounds and/or compositions of the invention are delivered by oralsustained release administration. Preferably, in this embodiment, thecompounds and/or compositions of the invention are administered twiceper day (more preferably, once per day).

4.6 Compositions of the Invention

The present compositions contain a therapeutically effective amount ofone or more compounds of the invention, preferably in purified form,together with a suitable amount of a pharmaceutically acceptablevehicle, to provide the form for proper administration to a patient.When administered to a patient, the compounds of the invention andpharmaceutically acceptable vehicles are preferably sterile. Water is apreferred vehicle when a compound of the invention is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles, particularly forinjectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propylene, glycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents. In addition, auxiliary, stabilizing, thickening,lubricating and coloring agents may be used.

In one embodiment, the compositions of the invention are free of lactamside products formed by intramolecular cyclization. In a preferredembodiment, the compositions of the invention are stable to extendedstorage (preferably, greater than one year) without substantial lactamformation (preferably, less than 0.5% lactam by weight, more preferably,less than 0.2% lactam by weight, most preferably, less than 0.1% lactamby weight).

Pharmaceutical compositions comprising a compound of the invention maybe manufactured by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or lyophilizing processes. Pharmaceutical compositions may beformulated in conventional manner using one or more physiologicallyacceptable carriers, diluents, excipients or auxiliaries, whichfacilitate processing of compounds of the invention into preparationswhich can be used pharmaceutically. Proper formulation is dependent uponthe route of administration chosen.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., Grosswald et al., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical vehicles have been described in theart (see Remington's Pharmaceutical Sciences, Philadelphia College ofPharmacy and Science, 17th Edition, 1985). Preferred compositions of theinvention are formulated for oral delivery, particularly for oralsustained release administration.

Compositions for oral delivery may be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions maycontain one or more optional agents, for example, sweetening agents suchas fructose, aspartame or saccharin, flavoring agents such aspeppermint, oil of wintergreen, or cherry coloring agents and preservingagents, to provide a pharmaceutically palatable preparation. Moreover,where in tablet or pill form, the compositions may be coated to delaydisintegration and absorption in the gastrointestinal tract, therebyproviding a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds andcompositions of the invention. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5 mM to about 50 mM), etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

Compositions for administration via other routes may also becontemplated. For buccal administration, the compositions may take theform of tablets, lozenges, etc. formulated in conventional manner.Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof the invention with a pharmaceutically acceptable vehicle. Preferably,the pharmaceutically acceptable vehicle is a liquid such as alcohol,water, polyethylene glycol or a perfluorocarbon. Optionally, anothermaterial may be added to alter the aerosol properties of the solution orsuspension of compounds of the invention. Preferably, this material isliquid such as an alcohol, glycol, polyglycol or a fatty acid. Othermethods of formulating liquid drug solutions or suspension suitable foruse in aerosol devices are known to those of skill in the art (see,e.g., Biesalski, U.S. Pat. No. 5,112,598; Biesalski, U.S. Pat. No.5,556,611). A compound of the invention may also be formulated in rectalor vaginal compositions such as suppositories or retention enemas, e.g.,containing conventional suppository bases such as cocoa butter or otherglycerides. In addition to the formulations described previously, acompound of the invention may also be formulated as a depot preparation.Such long acting formulations may be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, a compound of the invention may beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

When a compound of the invention is acidic, it may be included in any ofthe above-described formulations as the free acid, a pharmaceuticallyacceptable salt, a solvate or hydrate. Pharmaceutically acceptable saltssubstantially retain the activity of the free acid, may be prepared byreaction with bases and tend to be more soluble in aqueous and otherprotic solvents than the corresponding free acid form.

4.7 Methods of Use and Doses

A compound of the invention, or compositions thereof, will generally beused in an amount effective to achieve the intended purpose. For use totreat or prevent diseases or disorders such as epilepsy, depression,anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders,neurodegenerative disorders, panic, pain (especially neuropathic painand muscular and skeletal pain), inflammatory disease (i.e., arthritis),insomnia, gastrointestinal disorders or ethanol withdrawal syndrome thecompounds of the invention or compositions thereof, are administered orapplied in a therapeutically effective amount.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques known in the art as previouslydescribed. In addition, in vitro or in vivo assays may optionally beemployed to help identify optimal dosage ranges. The amount of acompound of the invention administered will, of course, be dependent on,among other factors, the subject being treated, the weight of thesubject, the severity of the affliction, the manner of administrationand the judgment of the prescribing physician.

For example, the dosage may be delivered in a pharmaceutical compositionby a single administration, by multiple applications or controlledrelease. In a preferred embodiment, the compounds of the invention aredelivered by oral sustained release administration. Preferably, in thisembodiment, the compounds of the invention are administered twice perday (more preferably, once per day). Dosing may be repeatedintermittently, may be provided alone or in combination with other drugsand may continue as long as required for effective treatment of thedisease state or disorder.

Suitable dosage ranges for oral administration are dependent on thepotency of the parent GABA analog drug, but are generally about 0.001 mgto about 200 mg of a compound of the invention per kilogram body weight.When the GABA analog is gabapentin, typical daily doses of the parentdrug in adult patients are 900 mg/day to 3600 mg/day and the dose ofgabapentin prodrug may be adjusted to provide an equivalent molarquantity of gabapentin. Other GABA analogs may be more potent thangabapentin (e.g., pregabalin), and lower doses may be appropriate forboth the parent drug and any prodrug (measured on an equivalent molarbasis). Dosage ranges may be readily determined by methods known to theskilled artisan.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetheradministration of a specific compound of the invention or a combinationof compounds of the invention is preferred for reducing convulsion. Thecompounds of the invention may also be demonstrated to be effective andsafe using animal model systems.

Preferably, a therapeutically effective dose of a compound of theinvention described herein will provide therapeutic benefit withoutcausing substantial toxicity. Toxicity of compounds of the invention maybe determined using standard pharmaceutical procedures and may bereadily ascertained by the skilled artisan. The dose ratio between toxicand therapeutic effect is the therapeutic index. A compound of theinvention will preferably exhibit particularly high therapeutic indicesin treating disease and disorders. The dosage of a compound of theinventions described herein will preferably be within a range ofcirculating concentrations that include an effective dose with little orno toxicity.

4.8. Combination Therapy

In certain embodiments of the present invention, the compounds of theinvention can be used in combination therapy with at least one othertherapeutic agent. The compound of the invention and the therapeuticagent can act additively or, more preferably, synergistically. In apreferred embodiment, a composition comprising a compound of theinvention is administered concurrently with the administration ofanother therapeutic agent, which can be part of the same composition asthe compound of the invention or a different composition. In anotherembodiment, a composition comprising a compound of the invention isadministered prior or subsequent to administration of anothertherapeutic agent.

5. EXAMPLES

The invention is further defined by reference to the following examples,which describe in detail preparation of compounds and compositions ofthe invention and assays for using compounds and compositions of theinvention. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the invention.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

AIBN = 2,2′-azobis(isobutyronitrile) Atm = atmosphere Boc =tert-butyloxycarbonyl Cbz = carbobenzyloxy CPM = counts per minute DCC =dicyclohexylcarbodiimide DMAP = 4-N,N-dimethylaminopyridine DMEM =Dulbecco's minimun eagle medium DMF = N,N-dimethylformamide DMSO =dimethylsulfoxide Fmoc = 9-fluorenylmethyloxycarbonyl g = gram h = hourHBSS = Hank's buffered saline solution L = liter LC/MS = liquidchromatography/mass spectroscopy M = molar min = minute mL = millilitermmol = millimoles NBS = N-bromosuccinimide NHS = N-hydroxysuccinimidePBS = phosphate buffered saline THF = tetrahydrofuran TFA =trifluoroacetic acid TMS = trimethylsilyl μL = microliter μM =micromolar v/v = volume to volume

Example 1 1-{[(α-Pivaloyloxymethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (51)

Step A: Chloromethyl p-Nitrophenyl Carbonate (52)

p-Nitrophenol (100 g, 0.72 moles) was dissolved in anhydroustetrahydrofuran (3 L) and stirred vigorously. To this solution was addedchloromethyl chloroformate (70 mL, 0.79 moles) at room temperaturefollowed by triethylamine (110 mL). After stirring for 1 hour, thereaction mixture was filtered and the filtrate was concentrated and thendiluted with ethyl acetate (1 L). The organic solution was washed with10% potassium carbonate (3×500 mL) and 1N HCl (2×300 mL), brine (2×300mL) and dried over anhydrous sodium sulfate. Removal of the solvent gave157 g (95%) of the title compound (52) as a solid. The compound wasunstable to LC-MS. ¹H NMR (CDCl₃, 400 MHz): 5.86 (s, 2H), 7.44 (d, J=9Hz, 2H), 8.33 (d, J=9 Hz, 2H).

Step B: Iodomethyl p-Nitrophenyl Carbonate (53)

Chloromethyl p-nitrophenyl carbonate (52) (100 g, 0.43 moles), sodiumiodide (228 g, 1.30 moles) and 50 g of dried molecular sieves (4 Å) wereadded to 2 L of acetone under nitrogen with mechanical stirring. Theresulting mixture was stirred at 40° C. for 5 hours (monitored by ¹HNMR). Upon completion, the solid materials were removed by filtrationand the solvent was removed under reduced pressure. The residue wasredissolved in dichloromethane (1 L) and washed twice with saturatedaqueous sodium carbonate (300 mL) followed by water (300 mL). Theorganic layer was separated and dried over anhydrous sodium sulfate.Removal of solvent gave 123.6 g (89%) of the title compound (53) as asolid upon standing. The compound was found to be unstable to LC-MS. ¹HNMR (CDCl₃, 400 MHz): 6.06 (s, 2H), 7.42 (d, J=9 Hz, 2H), 8.30 (d, J=9Hz, ¹³C NMR (CDCl₃, 100 MHz): 155.1, 151.0, 146.0, 125.8, 125.7, 121.9,33.5.

Step C: Silver Pivalate (54)

Pivalic acid (50 g, 0.49 moles) was dissolved in acetonitrile (1.3 L)followed by addition of silver oxide (70 g, 0.29 moles) with vigorousstirring. Then, 660 mL of water was added under nitrogen. The resultingsuspension was stirred at 70° C. in dark for 1 hour. After filtrationthrough a pad of Celite, removal of the solvent gave 86 g (82%) of thetitle compound (54) as a pale white solid, which was used in the nextreaction without further purification.

Other silver salts described in this application are prepared followingsimilar procedures.

Step D: p-Nitrophenyl Pivaloyloxymethyl Carbonate (55)

To a solution of iodomethyl p-nitrophenyl carbonate (53) (62 g, 0.19moles) in anhydrous toluene (1 L) was added silver pivalate (80 g, 0.38moles). After stirring at 55° C. under nitrogen for 3 h, the reactionmixture was allowed to cool to room temperature and filtered through apad of Celite. The filtrate was washed with 10% potassium carbonate (500mL). Removal of the solvent yielded 43 g (75%) of the title compound(55) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz): 1.25 (s, 9H), 5.88 (s,2H), 7.40 (d, J=9 Hz, 2H), 8.29 (d, J=9 Hz, 2H). ¹³C NMR (CDCl₃, 100MHz): 177.0, 155.3, 151.6, 145.8, 125.6, 121.9, 83.1, 39.1, 27.0.

Step E: 1-{[(α-Pivaloyloxymethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (51)

Gabapentin free base (24 g, 0.14 moles) was slurried in anhydrousdichloromethane (100 mL) and then treated with chlorotrimethylsilane(18.6 mL, 0.28 moles) and triethylamine (10 mL, 0.15 moles),respectively. The resulting suspension was warmed with stirring untilcomplete dissolution of any solid was achieved. The above gabapentinsolution was added via an equalizing addition funnel to a gentlyrefluxed and mechanically stirred solution of p-nitrophenylpivaloyloxymethyl carbonate (55) (20 g, 67 mmol) and triethylamine (10mL, 0.15 moles) in dichloromethane (100 mL) under nitrogen. Theresulting yellow solution was stirred for 1.5 hours. Upon completion(monitored by ninhydrin stain), the mixture was filtered and thefiltrate was concentrated. The residue was dissolved in ethyl acetate(500 mL) and washed with 1N HCl (3×100 mL), brine (2×100 mL) and driedover anhydrous sodium sulfate. After removing the solvent, the crudeproduct was dissolved in ethanol (300 mL) and then 1 g of 5% Pd/C wasadded. The resulting mixture was shaken under 50 psi hydrogen atmospherefor 15 minutes and then filtered through a pad of Celite. Afterconcentration, the residue was dissolved in ethyl acetate, washed with5% H₂SO₄ and dried over anhydrous sodium sulfate. After removing thesolvent under reduced pressure, the residue was purified bychromatography on silica gel (4:1 hexanes:ethyl acetate) to afford 15 g(68%) of the title compound (51) as a solid.

M.p.: 79-81° C.; ¹H NMR (CDCl₃, 400 MHz): 1.21 (s, 9H), 1.3-1.5 (m,10H), 2.32 (s, 2H), 3.26 (s, 2H), 5.33 (m, 1H), 5.73 (s, 2H). ¹³C NMR(CDCl₃, 400 MHz): 21.7, 26.2, 27.3, 34.3, 38.2, 39.2, 80.6, 155.9,176.8, 178.0. MS (ESI) m/z 328.36 (M−H)⁻, 330.32 (M+H)⁺, 352.33 (M+Na)⁺.

Example 2 1-{[(α-Acetoxyethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (56)

Step A: 1-Chloroethyl-p-Nitrophenyl Carbonate (57)

To an ice cold reaction mixture containing p-nitrophenol (1.39 g, 10mmol) and pyridine (0.81 g, 10 mmol) in dichloromethane (60 mL) wasadded 1-chloroethyl chloroformate (1.2 mL, 11 mmol). The mixture wasstirred at 0° C. for 30 min and then at room temperature for 1 hour.After removing the solvent under reduced pressure, the residue wasdissolved in ether, washed with water, 10% citric acid and water. Theether layer was dried over Na₂SO₄ and evaporated under reduced pressureto give 2.4 g (97%) of the title compound (57) as an off-white solid. ¹HNMR (CDCl₃): 1.93 (d, 3H), 6.55 (q, 1H), 7.42 (d, 2H), 8.28 (d, 2H).

Step B: α-Acetoxyethyl-p-Nitrophenyl Carbonate (58)

A mixture of 1-chloroethyl-p-nitrophenyl carbonate (57) (0.5 g, 2 mmol)and mercuric acetate (1.5 g, 4.4 mmol) in acetic acid (15 mL) wasstirred at room temperature for 24 hours. After removal of acetic acidunder reduced pressure, the residue was dissolved in ether and washedwith water, 0.5% (v/v) aqueous NaHCO₃, and water. The ether layer wasdried over Na₂SO₄, and concentrated to dryness. Chromatography of theresulting residue on silica gel, (hexanes:ethyl acetate (95:5)) gave0.45 g (84%) of the title compound (58). ¹H NMR (CDCl₃, 400 MHz): 1.55(d, J=5.6 Hz, 3H), 2.07 (s, 3H), 6.78 (q, J=5.6 Hz, 1H), 7.36 (d, J=9.6Hz, 2H), 8.22 (d, J=9.6 Hz, 2H).

Step C: 1-{[(α-Acetoxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (56)

To a mixture containing gabapentin (633 mg, 3.7 mmol) and triethylamine(1.03 mL, 7.4 mmol) in dichloromethane (20 mL) was addedtrimethylchlorosilane (0.93 mL, 7.4 mmol) and the mixture was stirreduntil a clear solution was formed. A solution containingα-acetoxyethyl-p-nitrophenyl carbonate (58) (1 g, 3.7 mmol) indichloromethane (10 mL) was then added and the resulting mixture wasstirred for 30 minutes. The reaction mixture was washed with 10% citricacid (20 mL) and the organic layer was separated. The aqueous layer wasfurther extracted with ether (3×10 mL) and the combined organic extractswere dried over MgSO₄. After filtration, the organic solvent was removedunder reduced pressure. Chromatography of the resulting residue onsilica gel, (hexanes:ethyl acetate (4:1)), gave 700 mg (63%) of thetitle compound (56). ¹H NMR (CDCl₃, 400 MHz): 1.27-1.60 (m, 10H), 1.55(d, 3H), 2.08 (s, 3H), 2.38 (s, 2H), 3.25 (m, 2H), 5.31 (t, 1H), 6.81(q, 1H). MS (ESI) m/z 302.22 (M+H)⁺. The acid form was quantitativelyconverted to the corresponding sodium salt by dissolution in water (5mL), addition of an equimolar quantity of 0.5 N NaHCO₃, followed bylyophilization.

Example 3 1-{[(α-Benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (59)

Step A: p-Nitrophenyl α-Benzoylbenzylcarbonate (60)

To a solution of benzoin (2.0 g, 9.4 mmol) in 60 mL of CH₂Cl₂ was addedDMAP (1.21 g, 9.9 mmol) and p-nitrophenyl-chloroformate (1.99 g, 9.9mmol), respectively, at room temperature. After stirring for 3 hours atroom temperature, the reaction was quenched with water and extractedwith ethyl acetate/hexane (2×100 mL). The combined organic extracts weredried over anhydrous sodium sulfate. Removal of the solvent underreduced pressure afforded the title compound (60), which was used in thenext reaction without purification.

Step B: 1-{[(α-Benzoylbenzyloxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (61)

To a suspension of gabapentin (1.70 g, 9.9 mmol) in CH₂Cl₂ at 0° C. wasadded triethylamine (2.76 mL, 19.8 mmol) and TMSCl (2.51 mL, 19.8 mmol).The reaction was then stirred for 30 minutes at room temperature. Tothis mixture was added compound (60) (prepared above in Step A) inCH₂Cl₂ and the resulting mixture was stirred at room temperature for 5hours. The reaction mixture was diluted with dichloromethane, washedwith brine and the organic phase was dried over Na₂SO₄. After removingthe solvent under reduced pressure, the residue was purified bychromatography on silica gel, eluting with 5% methanol in CH₂Cl₂, togive 3.78 g (90% over two steps) of the title compound (61). ¹H NMR(CDCl₃, 400 MHz): δ 1.48-1.35 (m, 10H), 2.30 (s, 2H), 3.24 (d, J=7.2 Hz,2H), 5.58 (t, J=6.8 Hz, 1H), 6.85 (s, 1H), 7.507.33 (m, 8H), 7.93 (d,J=7.2 Hz, 2H).

Step C: 1-{[(α-Benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (59)

To a solution of1-{[(α-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid(61) (1.89 g, 4.6 mmol) in 40 mL of CH₂Cl₂ was added 77% mCPBA (2.07 g,9.2 mmol) and NaHCO₃ (0.78 g, 9.2 mmol), respectively, at roomtemperature and the resulting mixture was stirred at room temperatureovernight. The reaction mixture was acidified with 10% citric acid andextracted with CH₂Cl₂. The organic extract was washed with brine anddried over Na₂SO₄. After removing the solvent under reduced pressure,the residue was purified by reverse phase preparative HPLC(acetonitrile-water, 0.1% formic acid) to afford 960 mg (49%) of thetitle compound (59). ¹H NMR (CDCl₃, 400 MHz): δ 1.58-1.35 (m, 10H), 2.34(s, 2H), 3.26 (dd, J=6.8, 0.8 Hz, 2H), 5.38 (t, J=6.8 Hz, 1H 7.46-7.26(m, 5H), 7.63-7.55 (m, 3H), 7.89 (s, 1H), 8.08 (dd, J=8.8, 1.2 Hz, 2H).

Example 4 1-{[(α-Acetoxybenzyloxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (62)

Following the procedure of Example 3, and substituting1-hydroxy-1-phenyl-propan-2-one for benzoin, provided 300 mg of thetitle compound (62). ¹H NMR (CDCl₃, 400 MHz): δ 1.41 (m, 10H), 2.19 (s,3H), 2.33 (s, 2H), 3.27 (dd, J=6.6, 1.6 Hz, 2H), 5.36 (t, J=6.6 Hz, 1H),7.40 (m, 3H), 7.52 (m, 2H), 7.63 (s, 1H).

Example 5 1-{[(α-Benzoyloxyethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (63)

Following the procedure of Example 3, and substituting2-hydroxy-1-phenyl-1-propanone for benzoin, provided 5 mg of the titlecompound (63). ¹H NMR (CDCl₃, 400 MHz): δ 1.44-1.36 (m, 10H), 1.62 (d,J=5.6 Hz, 3H), 2.34 (s, 2H), 3.24 (d, J=6.8 Hz, 2H), 5.28 (t, J=6.8 Hz,1 H), 7.06 (q, J=5.6 Hz, 1H), 7.44 (m, 2H), 7.56 (m, 1H), 8.03 (dd,J=8.4, 1.6 Hz, 2H).

Example 61-{[(1-Benzoyloxy-2-phenylethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (64)

Step A: 2-Phenyl-[1,3]-dithiane (65)

To a solution of benzaldehyde (10.6 g, 100 mmol) and 1,3-propane dithiolin CH₂Cl₂ (150 mL) at room temperature was dropwise added BF₃.Et₂O (6.3mL, 50 mmol) and the resulting mixture was stirred at room temperaturefor 2 hours. The reaction mixture was then diluted with CH₂Cl₂, filteredand the filtrate washed with brine, saturated NaHCO₃, brine and driedover Na₂SO₄. The solvent was removed under reduced pressure to afford awhite solid, which was recrystallized from a 1:1 mixture of ether andhexane to afford 17.0 g (87%) of the title compound (65) as whitecrystalline needles. ¹H NMR (CDCl₃, 400 MHz): δ 1.91 (m, 1H), 2.14 (m,1H), 2.89 (m, 2H), 3.04 (m, 2H), 5.16 (s, 1H), 7.35-7.28 (m, 3H), 7.46(m, 2H).

Step B: 2-Phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol (66)

To a solution of 2-phenyl-[1,3]-dithiane (65) (4.0 g, 20.4 mmol) in THFat −30° C. was added a 1.6 M solution of n-butyllithium in THF (15.3 mL,24.4 mmol). After stirring for 30 minutes at −30° C., a solution ofphenylacetylaldehyde (2.45 g, 20.4 mmol) in tetrahydrofuran was addeddropwise at −30° C. The resulting reaction mixture was stirred foranother hour at 0° C. The reaction was quenched with saturated NH₄Clsolution and extracted with ethyl acetate. The combined organic extractswere washed with saturated NH₄Cl solution, brine and dried over Na₂SO₄.After filtrating and concentrating, the crude product was purified byflash chromatography on silica gel, (25% ethyl acetate in hexanes), toafford 2.63 g (71%) of the title compound (66). ¹H NMR (CDCl₃, 400 MHz):δ 1.97 (m, 2H), 2.23 (dd, J=4.0, 1.2 Hz, 1H), 2.43 (dd, J=13.6, 10.2 Hz,1H), 2.77 (m, 4H), 3.02 (d, J=13.6 Hz, 1H), 4.07 (m, 1H), 7.44-7.13 (m,8H), 8.02 (dd, J=8.4, 1.4 Hz, 2H).

Step C: 2-Hydroxy-1,3-diphenyl-propan-1-one (67)

To a solution of 2-phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol (66)(2.50 g, 7.9 mmol) in 100 mL of a 9:1 mixture of acetonitrile and waterwas added mercuric perchlorate hydrate (4.1 g, 10.3 mmol). The resultingmixture was stirred at room temperature for 5 minutes and thin layerchromatography indicated that the reaction was completed. The mixturewas diluted with ethyl acetate, filtered through a pad of Celite and thefiltrate was washed with saturated NaHCO₃, brine and dried over Na₂SO₄.The solvent was removed under reduced pressure and the crude product waspurified by flash chromatography on silica gel, (20% ethyl acetate inhexanes) to afford 1.32 g (74%) of the title compound (67).

¹H NMR (CDCl₃, 400 MHz): δ 2.90 (dd, J=14.4, 7.0 Hz, 1H), 3.20 (dd,J=14.4, 4.0 Hz, 1H), 3.70 (d, J=6.8 Hz, 1H), 5.35 (m, 1H), 7.28-7.11 (m,5H), 7.53 (m, 2H), 7.65 (m, 1H), 7.93 (d, J=7.2 Hz, 2H).

Step D:1-{[(1-Benzoyloxy-2-phenylethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (64)

Following the procedure of Example 3, and substituting2-hydroxy-1,3-diphenyl-propan-1-one for benzoin, provided 181 mg of thetitle compound (64). ¹H NMR (CDCl₃, 400 MHz): δ 1.45-1.29 (m, 10H), 2.24(d, J=13.6 Hz, 1H), 2.28 (d, J=13.6 Hz, 1H), 3.22 (m, 4H), 5.26 (t,J=6.6 Hz, 1H), 7.16 (t, J=5.6 Hz, 1H), 7.33-7.25 (m, 5H), 7.40 (m, 2H),7.57 (m, 1H), 8.02 (m, 2H).

Example 71-{[(1-(3-Methylbutanoyloxy)-2-phenylethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (68)

Following the procedure of Example 6 and substituting3-methylbutyraldehyde for benzaldehyde in Step A, provided 95 mg of thetitle compound (68). ¹H NMR (CDCl₃, 400 MHz): δ 0.88-0.90 (m, 6H),1.16-1.29 (m, 10H), 2.06 (m, 1H), 2.16 (m, 2H), 2.26 (m, 2H), 3.08 (d,J=6.8 Hz, 2H), 3.19 (m, 2H), 5.22 (t, J=6.8 Hz, 1H), 6.93(t, J=6Hz, 1H),7.31-7.23 (m, 5H).

Example 8 1-{[(α-Benzoyloxybutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (69)

Following the procedure of Example 6 and substituting butyraldehyde forphenylacetaldehyde in Step B, provided 240 mg of the title compound(69). ¹H NMR (CDCl₃, 400 MHz): δ 0.99 (t, J=7.6 Hz, 3H), 1.52-1.38 (m,12H), 1.89 (m, 2H), 2.31 (s, 2H), 3.24 (m, 2H), 5.34 (t, J=6.6 Hz, 1H),6.70 (t, J=5.6 Hz, 1H), 7.42 (m, 2H), 7.56 (s, 1H), 8.04 (m, 2H).

Example 9 1-{[(α-Acetoxybutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (70)

Following the procedure of Example 6, and substituting acetaldehyde forbenzaldehyde in Step A and substituting butyraldehyde forphenylacetaldehyde in Step B respectively, provided 42 mg of the titlecompound (70). ¹H NMR (CD₃OD, 400 MHz): δ 0.95 (m, 3H), 1.52-1.31 (m,12H), 1.72 (m, 2H), 2.02 (s, 3H), 2.27 (s, 2H), 3.20 (s, 2H), 6.67 (t,J=5.6 Hz, 1H).

Example 10 1-{[(α-Butanoyloxybutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (71)

Following the procedure of Example 3, and substituting butyroin forbenzoin, provided 210 mg of the title compound (71). ¹H NMR (CDCl₃, 400MHz); δ 0.93 (m, 6H), 1.37-1.76 (m, 16H), 2.30 (m, 4H), 3.23 (m, 2H),5.25 (broad triplet, 1H), 6.73 (m, 1H). MS (ESI) m/z 356.45 (M−H)⁺.

Example 11 1-{[(α-Propanoyloxyethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (72)

Step A: 1-Iodoethyl-p-Nitrophenyl Carbonate (73)

A mixture of 1-chloroethyl-p-nitrophenyl carbonate (0.5 g, 2 mmol) andNaI (0.6 g, 4 mmol) in dry acetone was stirred for 3 hours at 40° C.After filtration, the filtrate was concentrated under reduced pressureto afford 480 mg (72%) of the title compound (73), which was used in thenext reaction without further purification.

Step B: α-Propanoyloxyethyl-p-Nitrophenyl Carbonate (74)

A mixture of 1-iodoethyl-p-nitrophenyl carbonate (73) (0.51 g, 1.5 mmol)and silver propionate (0.54 g, 3 mmol) in toluene (20 mL) was stirred at50° C. for 24 hours. The reaction mixture was filtered to remove solidsand the filtrate concentrated under reduced pressure. Chromatography ofthe resulting residue on silica gel, (20% CH₂Cl²/hexanes and then 40%CH₂Cl₂/hexanes), gave 0.39 g (92%) of the title compound (74). ¹H NMR(CDCl₃, 400 MHz): 1.16 (t, J=7.6 Hz, 3H), 1.61 (d, J=5.6 Hz, 3H), 2.41(q, J=7.6 Hz, 2H), 6.84 (q, 1H, J=5.6 Hz), 7.39 (d, J=9.2 Hz, 2H), 8.28(d, J=9.2 Hz, 2H).

Step C: 1-{[(α-Propanoyloxyethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (72)

To a mixture of gabapentin (160 mg, 2.76 mmol) and triethylamine (0.77mL, 5.5 mmol) in dichloromethane (30 mL) was added trimethylchlorosilane(0.71 mL, 5.5 mmol) and the resulting mixture was stirred until a clearsolution was formed. To the above solution was added a solution ofα-propanoyloxyethyl-p-nitrophenyl carbonate (74) (0.39 g, 1.4 mmol) indichloromethane (10 mL). After stirring for 30 minutes the reactionmixture was washed with 10% citric acid (20 mL) and the organic layerwas separated. The aqueous layer was further extracted with ether (3×10mL) and the combined organic extracts were dried over MgSO₄. Afterremoving the solvent under reduced pressure, the residue was purified byreverse phase preparative HPLC (acetonitrile, water, 1% formic acid) toafford 190 mg (44%) of the title compound (72). ¹H NMR (CD₃OD, 400 MHz):1.09 (t, J=7.6 Hz, 3H), 1.36-1.54 (m, 10H), 1.44 (d, J=5.6 Hz, 3H), 2.28(s, 2H), 2.31 (q, J=7.6 Hz, 2H), 3.22 (s, 2H), 6.67 (q, J=5.6 Hz, 1H).MS (ESI) m/z 316.25 (M+H)⁺.

Example 12 1-{[(α-Butanoyloxyethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (75)

Step A: α-Butanoyloxyethyl-p-Nitrophenyl Carbonate (76)

A mixture of 1-iodoethyl-p-nitrophenyl carbonate (73) (1.5 g, 4.5 mmol)and silver butyrate (1.3 g, 6.7 mmol) in toluene (40 mL) was stirred at90° C. in an oil bath for 24 h. The reaction mixture was filtered andthe filtrate was concentrated under reduced pressure. Chromatography ofthe resulting residue on silica gel, (20% CH₂Cl₂/hexanes and then 40%CH₂Cl₂/hexanes), gave 0.46 g (36%) of the title compound (76). ¹H NMR(CDCl₃, 400 MHz): 0.95 (t, J=7.6 Hz, 3H), 1.61 (d, J=5.6 Hz, 3H), 1.67(m, 2H), 2.41 (t, J=7.6 Hz, 2H), 6.84 (q, 1H, J=5.6 Hz), 7.39 (d, J=9.2Hz, 2H), 8.28 (d, J=9.2 Hz, 2H). MS (ESI) m/z 298.28 (M+H)⁺.

Step B: 1-{[(α-Butanoyloxyethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (75)

To a mixture containing gabapentin (530 mg, 3.1 mmol) and triethylamine(0.89 mL, 6.4 mmol) in dichloromethane (30 mL) was addedtrimethylchlorosilane (0.83 mL, 6.4 mmol) and the resulting mixture wasstirred until a clear solution was formed. To this solution was added asolution of α-butanoyloxyethyl-p-nitrophenyl carbonate (76) (0.46 g, 1.6mmol) in dichloromethane (10 mL) and the resulting mixture was stirredfor 30 min. The reaction mixture was washed with 10% citric acid (20 mL)and the organic phase was separated. The aqueous layer was furtherextracted with ether (3×10 mL) and the combined organic phases weredried over MgSO₄, then concentrated in vacuo. The resulting residue waspurified by reverse phase preparative HPLC (acetonitrile, water 0.1%formic acid) to afford 70 mg (21%) of the title compound (75). ¹H NMR(CD3OD, 400 MHz): 0.95 (t, J=7.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.42 (d,J=5.6 Hz, 3H), 1.67 (m, 2H), 2.24 (s, 2H), 2.30 (t, J=7.6 Hz, 2H), 3.24(s, 2H), 6.74 (q, J=5.6 Hz, 1H). MS (ESI) m/z 330.28 (M+H)⁺.

The acid form was quantitatively converted to the corresponding sodiumsalt by dissolution in water (5 mL), addition of an equimolar quantityof 0.5 N NaHCO₃, followed by lyophilization.

Example 131-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (77)

Following the procedure of Example 12, and substituting silverisobutyrate for silver butyrate, provided 70 mg (21%) of the titlecompound (77). ¹H NMR (CD₃OD, 400 MHz): 1.12 (d, J=7.2 Hz, 3H), 1.14 (d,J=7.2 Hz, 3H), 1.32-1.58 (m, 10H), 1.44 (d, J=5.6 Hz, 3H), 2.28 (s, 2H),2.56 (m, 1H), 3.25 (m, 2H), 6.73 (q, J=5.6 Hz, 1H). MS (ESI) m/z 330.30(M+H)⁺.

The acid form was quantitatively converted to the corresponding sodiumsalt by dissolution in water (5 mL), addition of an equimolar quantityof 0.5 N NaHCO₃, followed by lyophilization.

Example 14 1-{[(α-Pivaloxyethoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (78)

Following the procedure of Example 12, and substituting silver pivalatefor silver butyrate, provided 80 mg (36%) of the title compound (78). ¹HNMR (CDCl₃, 400 MHz): 1.13 (s, 9H), 1.32-1.58 (m, 10H), 1.41 (d, J=5.6Hz, 3H), 2.27 (s, 2H), 3.25 (m, 2H), 5.41 (t, 1H), 6.73 (q, J=5.6 Hz,1H). MS (ESI) m/z 344.20 (M+H)⁺.

The acid form was quantitatively converted to the corresponding sodiumsalt by dissolution in water (5 mL), addition of an equimolar quantityof 0.5 N NaHCO₃, followed by lyophilization.

Example 15 1-{[(α-Acetoxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (79)

Following the procedure of Example 2, and substituting1-chloro-2-methylpropyl chloroformate for 1-chloroethyl chloroformate,provided 212 mg (38%) of the title compound (79). ¹H NMR (CD₃OD, 400MHz): 0.99 (m, 6H), 1.32-1.58 (m, 10H), 1.88 (m, 1H), 2.08 (s, 3H), 2.38(s, 2H), 3.25 (s, 2H), 6.52 (d, J=4.4 Hz, 1H); MS (ESI) m/z 330.30(M+H)⁺.

Example 161-{[(α-Propanoyloxyisobutoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (80)

Following the procedure of Example 11, and substituting1-chloro-2-methylpropyl-p-nitrophenyl carbonate for1-chloroethyl-p-nitrophenyl carbonate, provided 190 mg (44%) of thetitle compounds (80). ¹H NMR (CD₃OD, 400 MHz): 0.90 (d, J=6.6 Hz, 3H),0.91 (d, J=6.6 Hz, 3H), 0.98 (t, J=7.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.83(m, 1H), 2.18 (s, 2H), 2.28 (q, J=7.6 Hz, 2H), 3.25 (s, 2H), 6.52 (d,J=4.4 Hz, 1H). MS (ESI) m/z 344.34 (M+H)⁺.

Example 171-{[(α-Butanoyloxyisobutoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (81)

Following the procedure of Example 2 and substituting1-chloro-2-methylpropyl chloroformate and mercuric butyrate for1-chloroethyl chloroformate and mercuric acetate, respectively, provided95 mg (36%) of the title compound (81). ¹H NMR (CD₃OD, 400 MHz): 1.12(t, J=7.6 Hz, 3H), 1.13 (d, J=6.6 Hz, 3H), 1.14 (d, J=6.6 Hz, 3H),1.32-1.58 (m, 10H), 1.87 (m, 2H), 2.22 (m, 1H), 2.42 (s, 2H), 2.46 (t,J=7.6 Hz, 2H), 3.44 (m, 2H), 6.78 (d, J=4.8 Hz, 1H). MS (ESI) m/z 358.30(M+H)⁺.

Example 181-{[(α-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (82)

Following the procedure of Example 2, and substituting1-chloro-2-methylpropyl chloroformate and mercuric isobutyrate for1-chloroethyl chloroform ate and mercuric acetate, respectively,provided 95 mg (36%) of the title compound (82). ¹H NMR (CD₃OD, 400MHz): 0.95 (d, J=7.2 Hz, 3H), 0.97 (d, J=7.2 Hz, 3H), 1.05 (d, J=6.6 Hz,3H), 1.06 (d, J=6.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.98 (m, 1H), 2.24 (s,2H), 2.45 (m, 1H), 3.24 (m, 2H), 6.42 (d, J=4.8 Hz, 1H). MS (ESI) m/z358.27 (M+H)⁺.

Example 19 1-{[(α-Pivaloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (83)

Following the procedure of Example 12, and substituting1-chloro-2-methylpropyl-p-nitrophenyl carbonate and silver pivalate for1-chloroethyl-p-nitrophenyl carbonate and silver butyrate, respectively,provided 10 mg (9%) of the title compound (83). ¹H NMR (CD₃OD, 400 MHz):0.98 (d, J=6.6 Hz, 3H), 0.99 (d, J=6.6Hz, 3H), 1.19 (s, 9H), 1.32-1.58(m, 10H), 2.08 (m, 1H), 2.28 (s, 2H), 3.21 (m, 2H), 6.49 (d, 1H); MS(ESI) m/z 372.31 (M+H)⁺.

Example 201-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (84)

Following the procedure of Example 11, and substituting1-chloro-2-methylpropyl-p-nitrophenyl carbonate and silver benzoate for1-chloroethyl 1-p-nitrophenyl carbonate and silver propionate,respectively, provided 109 mg (40%) of the title compound (84). ¹H NMR(CD₃OD, 400 MHz): 1.18 (d, J=7.2 Hz, 6H), 1.32-1.58 (m, 10 H), 2.42 (m,1H), 2.28 (s, 2H), 3.45 (s, 2H), 6.99 (d, J=4.8 Hz, 1H), 7.76 (m, 2H),7.92 (m, 1H), 8.26 (m, 2H). MS (ESI) m/z 392.22 (M+H)⁺.

Example 21 1-{[(α-Acetoxyisopropoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (85)

Step A: Isopropenyl-p-Nitrophenyl Carbonate (86)

To a mixture of p-nitrophenol (5.76 g, 41.5 mmol) and isopropenylchloroformate (5 g, 41.5 mmol) in dichloromethane (200 mL) at 0° C. wasadded a solution of pyridine (3.4 mL, 42 mmol) in dichloromethane (50mL). The resulting mixture was stirred at 0° C. for 30 minutes and thenat room temperature for 1 hour. After removing the solvent under reducedpressure, the residue was dissolved in ether and washed with water, 10%citric acid and water again. The ether layer was dried over Na₂SO₄ andevaporated under reduced pressure to give 8.7 g (94%) of the titlecompound (86) as an off-white solid. ¹H NMR (CDCl₃, 400 MHz): 2.05 (s,3H), 4.81 (m, 1H), 4.95 (d, J=2 Hz, 1H), 7.42 (d, J=9.2 Hz, 2H), 8.28(d, J=9.2 Hz, 2H).

Step B: 2-Chloroisopropyl-p-Nitrophenyl Carbonate (87)

Isopropenyl-p-nitrophenyl carbonate (86) (8.7 g, 39 mmol) was dissolvedin 4 M hydrogen chloride/dioxane in a sealed vessel. The mixture wasstirred at room temperature for 16 hours. Removal of the solvent underreduced pressure gave 10 g (100%) of the title compound (87), which wasused in the next reaction without further purification. ¹H NMR (CDCl₃,400 MHz): 2.10 (s, 6H), 7.42 (d, 2H, J=9.2 Hz), 8.28 (d, J=9.2 Hz, 2H).

Step C: α-Acetoxyisopropyl-p-Nitrophenyl Carbonate (88)

A mixture of 2-chloroisopropyl-p-nitrophenyl carbonate (87) (0.5 g, 1.93mmol) and mercuric acetate (1.0 g, 3.13 mmol) in dichloromethane (20 mL)was stirred at room temperature for 24 hours. The reaction mixture wasfiltered to remove solid and the filtrate concentrated under reducedpressure. Chromatography of the resulting residue on silica gel, (20%CH₂Cl₂/hexanes and then 40% CH₂Cl₂/hexanes), afforded 227 mg (50%) ofthe title compound (88). ¹H NMR (CDCl₃, 400 MHz): 1.90 (s, 6H), 2.07 (s,3H), 7.28 (d, 2H, J=9.2 Hz), 8.28 (d, J=9.2 Hz, 2H).

Step D: 1-{[(α-Acetoxyisopropoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (85)

To a mixture containing gabapentin (257 mg, 1.5 mmol) and triethylamine(0.46 mL, 3.3 mmol) in dichloromethane (30 mL) was addedtrimethylchlorosilane (0.38 mL, 3 mmol) and the mixture stirred untilclear. A solution containing α-acetoxyisopropyl-p-nitrophenyl carbonate(88) (0.23 g, 0.8 mmol) in dichloromethane (10 mL) was added and stirredfor 30 minutes. The reaction mixture was washed with brine (10 mL) andthe organic layer was separated. The aqueous layer was further extractedwith ether (3×10 mL) and the combined organic extracts were dried overMgSO₄ and then concentrated in vacuo. Chromatography of the resultingresidue on silica gel, (hexane:ethyl acetate (4:1)), gave 40 mg (16%) ofthe title compound (85). ¹H NMR (CD₃OD, 400 MHz): 1.32-1.58 (m, 10H),1.80 (s, 6H), 2.02 (s, 3H), 2.27 (s, 2H), 3.30 (s, 2H). MS (ESI) m/z316.21 (M+H)⁺.

Example 221-{[(α-Butanoyloxyisopropoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (89)

Following the procedure of Example 21, and substituting mercuricbutyrate for mercuric acetate, provided 5 mg (5%) of the title compound(89). ¹H NMR (CD₃OD, 400 MHz): 0.99 (t, J=7.6 Hz, 3H), 1.32-1.58 (m,10H), 1.60 (m, 2H), 1.85 (s, 6H), 2.2 (t, J=7.6, 2H), 2.27 (s, 2H), 3.20(s, 2H). MS (ESI) m/z 344.24 (M+H)⁺, 366.30 (M+Na)⁺.

Example 231-{[(α-Isobutanoyloxyisopropoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (90)

Following the procedure of Example 21, and substituting mercuricisobutyrate for mercuric acetate, provided 109 mg (43%) of the titlecompound (90). ¹H NMR (CD₃OD, 400 MHz): 1.19 (d. J=7.2 Hz, 6H),1.32-1.58 (m, 10H), 1.82 (s, 6H), 2.38 (s, 2H), 3.25 (s, 2H). MS (ESI)344.22 (M+H)⁺, 366.24 (M+Na)⁺.

Example 241-{[(α-Benzoyloxyisopropoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (91)

Following the procedure of Example 21, and substituting mercuricbenzoate for mercuric acetate, provided 170 mg (58%) of the titlecompound (91). ¹H NMR (CDCl₃, 400 MHz): 1.32-1.58 (m, 10H), 1.95 (s,6H), 2.30 (s, 2H), 3.20 (d, J=6.8, 2H), 5.41 (t, J=6.8 Hz, 1H), 7.40 (m,2H), 7.52 (m, 1H), 7.98 (m, 2H). MS (ESI) m/z 400.29 (M+Na)⁺.

Example 251-{[(α-Nicotinoyloxyisobutoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (92)

Step A: 1-{[(α-Chloroisobutoxy)carbonyl]aminomethyl-1-Cyclohexane AceticAcid (93)

To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine(3.06 mL, 22 mmol) in dichloromethane (150 mL) was addedtrimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture wasstirred until clear (about 20 min). A solution containing1-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) indichloromethane (10 mL) was then added at 0° C. and stirred at roomtemperature for 60 min. The reaction mixture was washed with 10% citricacid (30 mL) and the organic layer separated. The aqueous layer wasfurther extracted with ether (3×20 mL) and the combined organic phaseswere dried over MgSO₄ and then concentrated in vacuo. Chromatography ofthe residue on silica gel, eluting with hexane:ethyl acetate (1:4) gave2.37 g (77%) of the title compound.

¹H NMR (CDCl₃, 400 MHz): δ 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz,3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39(t, 1H), 6.32 (d, J=5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H⁺).

Step B:1-{[(α-Nicotinoyloxyisobutoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (92)

A mixture of (93) (268 mg, 0.88 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (158 μL, 1.01 mmol), andnicotinic acid (637 mg, 5.2 mmol) in acetone was stirred at roomtemperature for 48 h. After filtration, the filtrate was concentrated invacuo and the resulting residue was purified by reverse phasepreparative HPLC to afford 50 mg (14%) of the title compound. ¹H NMR(CD₃OD, 400 MHz): δ 1.07 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H),1.32-1.58 (m, 10H), 2.19 (m, 1H), 2.26 (s, 2H), 3.23 (m, 2H), 6.78 (d,J=4.8 Hz, 1H), 7.58 (m, 1H), 8.39 (d, J=6.4 Hz, 1H), 8.76 (d, J=4.4 Hz,1H), 9.10 (s, 1H). MS (ESI) m/z 393.42 (M+H⁺).

Example 261-{[(α-2,2-Diethoxypropanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (94)

Step A: Benzyl1-{[(α-Chloroisobutoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetate (95)

To a solution of (93) (1.02 g, 3.34 mmol) in dichloromethane was added1,3-dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring at roomtemperature for 30 min, benzyl alcohol (380 μL, 3.67 mmol) and4-(dimethylamino)pyridine (catalytic amount) were added. The resultingmixture was stirred at room temperature of 16 h. After filtration, thefiltrate was washed with 10% citric acid, dried over Na₂SO₄, andconcentrated. Chromatography of the residue on silica gel, eluting with10% ethyl acetate/hexane, gave 820 mg (62%) of the title compound. ¹HNMR (CDCl₃, 400 MHz): δ 1.03 (d, J=6.4 Hz, 3H), 1.05(d, J=6.4 Hz, 3H),1.36-1.53 (m, 10H), 2.13 (m, 1H), 2.35 (s, 2H), 3.22 (m, 2H), 5.11 (s,2H), 5.49 (t, 1H), 6.32 (d, J=4.8 Hz), 1H), 7.34 (m, 5H). MS (ESI) m/z396.24 (M+H⁺).

Step B: Cesium 2,2-Diethoxypropionate (96)

To a stirred solution of 14 mL (0.2 mol) of pyruvic acid and 80 mL oftriethylorthoformate at 10° C. was added 1 mL of concentrated sulfuricacid. The resulting mixture was stirred at 5-10° C. for 1 h and thendiluted with 200 mL of dichloromethane. The organic solution was washedsuccessively with water (3×80 mL) and saturated sodium chloride solution(80 mL) and then dried over anhydrous sodium sulfate. The mixture wasfiltered and then concentrated to give a quantitative yield of2,2-diethoxypropionic acid as an oil. ¹H NMR (CDCl₃, 400 MHz): δ 1.30(t, 6H), 1.61 (s, 3H), 3.57 (q, 4H), 8.62 (s, 1H). The acid form wasquantitatively converted to its cesium salt by dissolving the acid inwater (25 mL) followed by treatment with an equimolar quantity of cesiumcarbonate, and then lyophilization. ¹H NMR (D₂O, 400 MHz): δ 0.98 (t,6H), 1.28 (s, 3H), 3.22 (q, 2H), 3.47 (q, 2H).

Step C: Benzyl1-{[(α-2,2-Diethoxypropanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetate (97)

A mixture of (95) (200 mg, 0.51 mmol) and sodium iodide (114 mg, 0.76mmol) in acetone was stirred at room temperature for 1 h. Cesium2,2-diethoxypropionate (96) (300 mg, 1.02 mmol) and DMF (20 mL) wereadded and the resulting mixture was stirred at 40° C. for 18 h. Afterfiltration, the filtrate was concentrated and the resulting residue waspurified by silica gel flash column chromatography, eluting with 10%ethyl acetate/hexane to afford 100 mg (37%) of the title compound. MS(ESI) m/z 522.34 (M+H⁺).

Step D:1-{[(α-2,2-Diethoxypropanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (94)

A mixture of (97) (200 mg, 0.38 mmol) and 5% Pd—C (catalytically amount)was stirred under hydrogen at room temperature for 16 h. Afterfiltration, the filtrate was concentrated and the resulting residue waspurified by reverse phase preparative HPLC to afford 98 mg (60%) of thetitle compound. ¹H NMR (CDCl₃, 400 MHz): δ 0.97 (d, J=6.8 Hz, 6H), 1.19(t, J=6.4 Hz, 3H), 1.21 (t, J=6.4 Hz, 3H), 1.32-1.58 (m, 10H), 1.5 (s,3H), 2.06 (m, 1H), 2.30 (s, 2H), 3.23 (m, 2H), 3.46 (m, 2H), 3.56 (m,2H), 5.30 (t, 1H, NH), 6.59 (d, J=4.8 Hz, 1H). MS (ESI) m/z 432.24(M+H⁺).

Example 271-{[(α-(2-Amino-2-methylpropanoyl)oxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (98)

Following the procedure of Example 26, and substituting2-amino-2-methylpropionic acid for 2,2-diethoxypropionic acid, providedthe title compound. ¹H NMR (CDCl₃, 400 MHz): δ 0.97 (d, J=6.8 Hz, 6H),1.44 (s, 3H), 1.45 (s 3H), 1.32-1.58 (m, 10H), 2.05 (m, 1H), 2.30 (s,2H), 3.23 (m, 2H), 5.50 (t, 1H, NH), 6.58 (d, J=4.8 Hz, 1H). MS (ESI)m/z 373.48 (M+H⁺).

Example 281-{[(α-Isobutanoyloxybutoxy)carbonyl]aminomethyl}-1-Cyclohexane AceticAcid (99)

Step A: 2-Isopropyl-1,3-Dithiane (100)

To a mixture of isobutyraldehyde (9.1 mL, 100 mmol) and1,3-propanedithiol (10 mL, 100 mmol) in dichloromethane at 0° C. wasadded boron trifluoride diethyl etherate (6.4 mL, 50 mmol). Theresulting mixture was stirred at 0° C. for 30 min and at roomtemperature for 30 min. The reaction mixture was washed with brine, 5%NaHCO₃, and brine again. The organic phase was separated and dried overNa₂SO₄, then concentrated to give 16 g (100%) of the title compound as ayellow liquid. This was carried to the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz): δ 1.057 (d, J=7.2 Hz, 3H), 1.059(d, J=7.2 Hz, 3H), 1.80 (m, 1H), 1.97-2.08 (m, 2H), 2.82 (m, 4H), 4.00(d, J=5.2 Hz, 1H).

Step B: 2-Isopropyl-2-(α-Hydroxybutyl)-1,3-Dithiane (101)

To a solution of (100) (4 g, 24.7 mmol) in anhydrous tetrahydrofuran (50mL) at −20° C. was dropwise added n-butyl lithium (1.6M in hexane, 18.5mL, 29.6 mmol). The stirred mixture was allowed to warm room temperatureover 4 h and then cooled to −20° C. again. To this solution was addedslowly a solution of n-butyraldehyde (2.7 mL, 29.6 mmol) in anhydroustetrahydrofuran (10 mL). The resulting mixture was stirred for 16 hbetween −20° C. and room temperature. The reaction was quenched withsaturated ammonium chloride solution and the mixture extracted withethyl acetate. The organic layer was separated and dried over Na₂SO₄.After removing the solvent under reduced pressure, flash columnchromatography of the residue on silica gel, eluting with 5% ethylacetate/hexane provided 5 g (85%) of the title compound as a yellow oil.¹H NMR (CDCl₃, 400 MHz): δ 0.96 (t, J=7.2 Hz, 3H), 1.11 (d, J=6.8, Hz,3H), 1.17 (d, J=6.8 H, 3H), 1.42-1.52 (m, 2H), 1.76 (m, 1H), 1.87-1.95(m, 2H), 2.04 (m, 2H), 2.62 (m, 4H), 2.94 (m, 2H), 4.03 (d, J=5.2 Hz,1H).

Step C: 4-Hydroxy-2-Methylheptan-3-one (102)

To a solution of (101) (5.0 g, 21.4 mmol) in acetonitrile (270 mL) wasadded under vigorous stirring a solution of Hg(ClO₄)₂ in methanol (30mL). The resulting mixture was stirred at room temperature for 2 h.After filtration, the filtrate was carefully concentrated under reducedpressure without heating. Purification of the residue using silica gelflash column chromatography (10% ethyl acetate/hexane) provided 2.8 g(91%) of the title compound as colorless liquid. ¹H NMR (CDCl₃, 400MHz): δ 0.91 (t, J=7.2 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H), 1.10 (d, J=7.2Hz, 3H), 1.35-1.46 (m, 4H), 1.75 (m, 1H), 2.80 (m, 1H), 3.45 (d, J=5.2Hz, 1H), 4.29 (m, 1H).

Step D: 2-Methylheptan-3-one-4-p-Nitrophenyl Carbonate (103)

To a mixture of (102) (1.1 g, 7.6 mmol), p-nitrophenyl chloroformate(1.84 g, 9.2 mmol) in anhydrous dichloromethane at 0° C. was addedslowly a solution of 4-dimethylaminopyridine (1.12 g, 9.2 mmol) indichloromethane. After stirring for 1 h at 0° C. and for 4 h at roomtemperature, the reaction was quenched with 10% citric acid. The organicphase was separated, dried over Na₂SO₄, and concentrated in vacuo. Flashcolumn chromatography of the residue, eluting with 30%dichloromethaneihexane, provided 2 g (85%) of the title compound as anoff-white solid. ¹H NMR (CDCl₃, 400 MHz): δ 0.99 (t, J=7.6 Hz, 3H), 1.12(d, J=6.8 Hz, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.51 (m, 2H), 1.84 (m, 2H),2.82 (m, 1H), 5.17 (m, 1H), 7.42 (d, J=6.8 Hz, 2H), 8.25 (d, J=6.8 Hz,2H).

Step E: 1-{[(α-Isobutanoylbutxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (104)

To a mixture containing gabapentin (820 mg, 4.8 mmol) and triethylamine(1.35 mL, 9.6 mmol) in dichloromethane (20 mL) was addedtrimethylchlorosilane (1.22 mL, 9.6 mmol) and the resulting mixture wasstirred for 20 min. To this solution was added (103) (1 g, 3.2 mmol) indichloromethane (10 mL) and the resulting mixture was stirred for 60min. The reaction mixture was washed with 10% citric acid (20 mL) andthe organic layer separated. The aqueous layer was further extractedwith ether (3×10 mL) and the combined organic extracts were dried overMgSO₄ then concentrated in vacuo. Chromatography of the residue onsilica gel, eluting with hexane:ethyl acetate (4:1) to removep-nitrophenol, then further eluting with hexane:ethyl acetate (1:4) gave780 mg (72%) of the title compound. ¹H NMR (CDCl₃, 400 MHz): δ 0.91 (t,J=7.2 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.8 Hz, 3H), 1.36-1.53(m, 12H), 1.74 (m, 2H), 2.33 (s, 2H), 2.78 (m, 1H), 3.22 (m, 2H), 5.11(m, 1H), 5.48 (t, 1H, NH). MS (ESI) m/z 342.24 (M+H⁺).

Step F: 1-{[(α-Isobutanoyloxybutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (99)

To a solution of (104) (780 mg, 2.3 mmol) in dichloromethane (20 mL) wasadded m-chloroperoxybenzoic acid (1.03 g, 4.6 mmol) and NaHCO₃ (386 mg,4.6 mmol). After stirring for 16 h at room temperature, another batch ofm-chloroperoxybenzoic acid (791 mg, 4.6 mmol) and NaHCO₃ (386 mg, 4.6mmol) was added. The resulting mixture was stirred for another 8 h andthen treated with 10% citric acid. After filtration, the organic layerwas separated, dried over Na₂SO₄, and concentrated. The residue waspurified by reverse phase preparative HPLC to afford 79 mg (11%) of thetitle compound. ¹H NMR (CDCl₃, 400 MHz): δ 0.94 (t, J=7.2 Hz, 3H), 1.153(d, J=7.2 Hz, 3H), 1.150 (d, J=7.2 Hz, 3H), 1.32-1.58 (m, 12H), 1.74 (m,2H), 2.28 (s, 2H), 2.56 (m, 1H), 3.23 (m, 2H), 5.27 (t, J=6.8 Hz, 1H,NH), 6.71 (t, J=5.6 Hz, 1H). MS (ESI) m/z 358.30 (M+H⁺).

The above acid was quantitatively converted to the corresponding sodiumsalt by dissolving the acid in water (5 mL) followed by addition of anequimolar quantity of 0.5 N NaHCO₃ and lyophilization.

Example 29 Methyl1-{[(α-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetate (105)

Step A: Methyl1-{[(α-Chloroisobutoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetate (106)

A mixture of (93) (1.0 g, 3.3 mmol), benzene (90 mL), and methanol (10mL) was cooled to 0° C. Trimethylsilyldiazomethane was added slowly at0° C. until the yellow color persisted. The mixture was stirred at 0° C.for 30 min until the reaction was complete (monitored by TLC). Afterremoving the solvent under reduced pressure, chromatography of theresulting residue on silica gel, eluting with 10% ethyl acetate/hexanegave 760 mg (72%) of the title compound. MS (ESI) m/z 320.24 (M+H⁺).

Step B: Methyl1-{[(α-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetate (105)

A mixture of (106) (760 mg, 2.38 mmol), silver carbonate (394 mg, 1.4mmol), and isobutyric acid (442 μL, 4.76 mmol) in chloroform was stirredat room temperature for 24 h. Another batch of silver carbonate (394 mg,1.4 mmol) and isobutyric acid (442 μL, 4.76 mmol) was added, and theresulting mixture was stirred for another 24 h. After filtration, thefiltrate was concentrated and the resulting residue purified by silicagel flash column chromatography, eluting with 10% ethyl acetate/hexane,to afford 560 mg (63%) of the title compound. ¹H NMR (CDCl₃, 400 MHz): δ0.94 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H),1.15 (d, J=7.2 Hz, 3H), 1.17 (d, J=7.2 Hz, 3H), 1.32-1.58 (m, 10H), 2.01(m, 1H), 2.19 (s, 2H), 2.55 (m, 1H), 3.18 (m, 2H), 3.67 (s, 3H), 5.33(t, 1H), 6.56 (d, J=4.8 Hz, 1H). MS (ESI) m/z 372.38 (M+H⁺).

Example 30 Methyl1-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-Cyclohexane Acetate(107)

A mixture of1-{[(α-benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane aceticacid (84) (150 mg, 0.38 mmol), benzene (18 mL), and methanol (2 mL) wascooled to 0° C. Trimethylsilyldiazomethane was added slowly at 0° C.until the yellow color persisted. The mixture was stirred at 0° C. for30 min until the reaction was complete (monitored by TLC). Afterremoving the solvent under reduced pressure, chromatography of theresidue on silica gel, eluting with 5% ethyl acetate/hexane gave 98 mg(64%) of the title compound.

¹H NMR (CDCl₃, 400 MHz): δ 1.02 (d, J=6.4 Hz, 3H), 1.03 (d, J=6.4 Hz,3H), 1.32-1.52 (m, 10H), 2.14 (m, 1H), 2.27 (s, 2H), 3.17 (m, 2H), 3.62(s, 3H), 5.40 (t, 1H), 6.81 (d, J=4.8 Hz, 1H), 7.40 (m, 2H), 7.54 (m,1H), 8.12 (m, 2H). MS (ESI) m/z 406.29 (M+H⁺).

Example 311-{[N-[(α-Isobutanoyloxyethoxy)carbonyl]-4-Bromophenylalaninyl]aminomethyl}-1-CyclohexaneAcetic Acid (108)

Step A: 1-{(4-Bromophenylalaninyl)aminomethyl}-1-Cyclohexane Acetate(109)

To a 40 mL vial was added an N-Boc-4-bromophenylalanine (1.72 g, 5mmol), dicyclohexylcarbodiimide (1.24 g, 6 mmol), N-hydroxysuccinimide(0.7 g, 6 mmol), and acetonitrile (20 mL). The reaction mixture wasshaken at 25° C. for 4 h. The precipitated dicyclohexylurea was removedby filtration. To the filtrate was added an aqueous solution (30 mL) ofgabapentin hydrochloride (1.04 g, 6 mmol), and sodium hydroxide (0.4 g,10 mmol). The reaction was stirred at 22-25 C. for 16 h. The reactionmixture was diluted with ethyl acetate (100 mL) and washed with 0.5 Maqueous citric acid (2×100 mL) and water (2×100 mL). The organic phasewas separated, dried (MgSO₄), filtered and concentrated under reducedpressure. The residue was dissolved in trifluoroacetic acid (40 mL) andallowed to stand at 22-25° C. for 2 h. The solvent was removed underreduced pressure. The residue was dissolved in water (4 mL) and filteredthrough a 0.25 μm nylon membrane filter prior to purification bypreparative HPLC (Phenomenex 250×21.2 mm, 5 μm LUNA C18 column, 100%water for 5 minutes, then 0-60% acetonitrile in water with 0.05% TFAover 20 minutes at 20 mL/min). The pure fractions were combined and thesolvent was removed under reduced pressure to afford 1.7 g (70%) of thetitle compound (109) as a white solid. MS (ESI) m/z 397.02, 399.01(M+H⁺).

Step B:1-{[N-[(α-Isobutanoyloxyethoxy)carbonyl]-4-Bromophenylalaninyl]aminomethyl}-1-CyclohexaneAcetic Acid (108)

To a stirred suspension of (109) (200 mg, 0.51 mmol) in dichloromethaneat 0° C. was added triethylamine (141 μL, 1.01 mmol) andtrimethylchlorosilane (129 mL, 1.01 mmol). The resulting mixture wasstirred for 15 min at 0° C., then a solution ofα-isobutanoyloxyethyl-p-nitrophenyl carbonate (111) (144 mg, 0.51 mmol)in dichloromethane was added. The mixture was stirred at roomtemperature for 7 h (monitored by LC/MS) and then the reaction mixturewas diluted with dichloromethane and acidified with citric acid. Theorganic layer was separated, washed with brine, and dried over Na₂SO₄.After filtration and concentration, the crude product was purified bypreparative LC/MS to afford 92 mg of the title compound. ¹H-NMR (CD₃OD,400 MHz): δ 1.10 (m, 6H), 1.46-1.25 (m, 13 H), 2.20 (m, 2H), 2.48 (m,1H), 2.84 (m, 1H), 3.06 (m, 1H), 3.17 (m, 1H), 4.36 (m, 1H), 6.67 (q,J=5.6 Hz, 1H), 7.17 (d, J=2.0, 8.0 Hz, 2H), 7.42 (dd, J=2.0, 8.0 Hz,2H).

Example 323-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-Methylhexanoic Acid(110)

Step A: α-Isobutanoyloxyethyl-p-Nitrophenyl Carbonate (111)

A solution of 1-chloroethyl-p-nitrophenyl carbonate (57) (2.0 g, 8.14mmol), and mercury isobutyrate (6.13 g, 16.29 mmol) in dichloromethane(10 mL) was stirred at 45° C. for 24 h. The reaction was then cooled toroom temperature and diluted with hexane to precipitate mercury salts.The precipitate was filtered through a pad of Celite, and the filtratewas concentrated in vacuo to afford 2.5 g of crude product.Chromatography of the residue on silica gel, eluting with a gradient of10% dichloromethane/hexane to 20% dichloromethane/hexane afforded 1.2 g(52%) of the title compound. ¹H-NMR (CDCl₃, 400 MHz): δ 1.21-1.99 (m,6H), 1.62 (d, J=5.6 Hz, 3H), 2.61 (m, 1H), 6.84 (q, J=5.6 Hz, 1H), 7.41(dt, J=6.8, 2.4 Hz, 2H). 8.29 (J=6.8, 2.4 Hz, 2H).

Step B:3-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-Methylhexanoic Acid(110)

To a stirred suspension of pregabalin (2) (150 mg, 0.94 mmol) inanhydrous dichloromethane (10 mL) at 0° C. was added triethylamine (0.26mL, 1.88 mmol) and trimethylchlorosilane (0.24 mL, 1.88 mmol). Afterstirring for 15 min at 0° C., a solution ofα-isobutanoyloxyethyl-p-nitrophenyl carbonate (111) (267 mg, 0.94 mmol)in dichloromethane (3 mL) was added. The resulting mixture was stirredat room temperature for 1.5 h. The reaction mixture was acidified withcitric acid and extracted with dichloromethane. The combined organicextracts were washed with brine and dried over Na₂SO₄. After filtrationand evaporation, the crude product was purified by silica gelchromatography, eluting first with dichloromethane to removenitrophenol, then with 30% ethyl acetate in dichloromethane to afford130 mg (48%) of the title compound as a mixture of two diastereomers.¹H-NMR (CDCl₃, 400 MHz): δ 0.90 (m, 6H), 1.70 (m, 8H), 1.46 (d, J=5.6Hz, 3H), 1.66 (1H, m), 2.15 (m, 1H), 2.33 (m, 2H), 2.53 (m, 1H), 3.12(m, 1H), 3.29 (m, 1H), 5.08 (t, J=6.0 Hz, 1H), 6.79 (m, 1H).

Example 333-{[(α-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-5-Methyl-HexanoicAcid (112)

Step A: 1-Chloro-2-Methylpropyl-p-Nitrophenyl Carbonate (113)

To an ice cold reaction mixture containing p-nitrophenol (4.06 g, 29mmol) and 1-chloro-2-methylpropyl chloroformate (5.0 g, 29 mmol) indichloromethane (200 mL) was added a solution of pyridine (2.78 mL, 32mmol) in dichloromethane (50 mL). The mixture was stirred at 0° C. for30 min and then at room temperature for 1 h. After evaporation of thesolvent under reduced pressure, the residue was dissolved in ether andwashed with water, 10% citric acid and water again. The ether layer wasseparated, dried over Na₂SO₄ and evaporated under reduced pressure togive 7.9 g (100%) of the title compound as an off-white solid. ¹H NMR(CDCl₃, 400 MHz): δ 1.12 (d, J=6.6 Hz, 3H), 1.13 (d, J=6.6 Hz, 3H), 2.29(m, 1H), 6.24 (d, J=4.8 Hz, 1H), 7.42 (d, J=9.2 Hz, 2H), 8.28 (d,J=9.2Hz, 2H).

Step B: α-Isobutanoyloxyisobutyl-p-Nitrophenyl Carbonate (114)

Following the procedure for preparation of (111), and substituting (113)for (57), provided the title compound in 15% yield with a 70% recoveryof starting material. ¹H-NMR (CDCl₃, 400 MHz): δ 1.07 (d, J=6.8 Hz),1.21 (m, 6H), 2.18 (m, 1H), 2.26 (m, 1H), 6.60 (d, J=5.2 Hz, 1H), 7.42(m, 2H), 8.28 (m, 2H).

Step C:3-{[(α-Isobutanoyloxyisobutoxy)carbonyl]aminomethyl}-5-Methyl-HexanoicAcid (112)

Following the procedure of preparation for (110), and substituting (114)for (111), provided the title compound as a mixture of two diastereomersin 51% yild. ¹H-NMR (CDCl₃, 400 MHz): δ 0.89 (m, 12H), 1.17 (m, 8H),1.65 (m, 1H), 2.02 (m, 1H), 2.16 (m, 1H), 2.33 (m, 2H), 2.56 (m, 1H),3.13 (m, 1H), 3.30 (m, 1H), 5.00 (m, 1H), 6.57-6.56 (m, 1H).

Example 343-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-5-Methyl-Hexanoic Acid(115)

Step A: α-Benzoyloxyisobutyl-p-Nitrophenyl Carbonate (116)

Following the procedure of preparation for (111), substituting (113) for(57) and mercury benzoate for mercury isobutyrate, provided the titlecompound in 11% yield with a 50% recovery of starting material. ¹H-NMR(CDCl₃, 400 MHz): 61.15 (d, J=3.2 Hz, 3H), 1.16 (d, J=3.2 Hz, 3H), 2.30(m, 1H), 6.87 (d, J=4.4 Hz, 1H), 7.42 (dd, J=7.2, 2.0 Hz, 2H), 7.48 (t,J=7.6 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 8.09 (dd, J=8.0, 1.0 Hz, 2H),8.27 (dd, J=7.2, 2.0 Hz, 2H).

Step B:3-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-5-Methyl-Hexanoic Acid(115)

Following the procedure of preparation for (110), and substituting (116)for (111), provided the title compound as a mixture of two diastereomersin 58% yield. ¹H-NMR (CDCl₃, 400 MHz): δ 0.87(m, 6H), 1.05 (m, 6H), 1.16(m, 2H), 1.64 (m, 1H), 2.17 (m, 2H), 2.32 (m, 2H), 3.12 (m, 1H), 3.29(m, 1H), 5.01 (br s, 1H), 6.82 (m, 1H), 7.44 (m, 2H), 7.57 (m, 1H), 8.05(m, 2H).

Example 351-{[((5-Methyl-2-Oxo-1,3-Dioxol-4-en-4-yl)methoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (117)

Step A: Benzyl 2-Diazo-3-Oxo-Butyric Acid (118)

To a solution of benzyl acetoacetate (5.0 g, 26.01 mmol) and4-acetamido-benzenesulfonyl azide (6.25 g, 26.01 mmol) in acetonitrile(200 mL) at 0° C. was dropwise added triethylamine (10.9 mL, 78.03mmol). The resulting mixture was stirred for 30 min at 0° C. and 4 h atroom temperature. After concentrating under reduced pressure, theresidue was triturated with 2:1 ethyl ether/petroleum ether (3×100 mL).The combined organic extract was filtered through a pad of Celite toppedwith silica gel. Removal of the solvent under reduced pressure afforded4.74 g of the title compound as off-white crystals. ¹H-NMR (CDCl₃, 400MHz): δ 2.49 (s, 3H), 5.27 (s, 2H), 7.38 (m, 5H).

Step B: Benzyl 2-Hydroxy-3-Oxo-Butyric Acid (119)

A solution of the diazo compound (118) (4.74 g, 21.74 mmol) in THF (110mL) and H₂O (50 mL) was heated under reflux with Rh₂(OAc)₂ (77 mg, 0.17mmol) for 4 h and allowed to cool to room temperature. The mixture wasconcentrated in vacuo and the aqueous residue was extracted with ethylacetate. The combined organic extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo to provide 4.5 g ofcrude product. ¹H-NMR (CDCl₃, 400 MHz): δ 2.28 (s, 3H), 3.90 (s, 1H),4.82 (s, 1H), 5.26 (m, 2H), 7.37 (m, 5H).

Step C: 4-Benzyloxycarbonyl 5-Methyl-2-Oxo-1,3-Dioxol-4-ene (120)

To a suspension of carbonyldiimidazole (6.88 g, 42.45 mmol) in THF (50mL) at 0° C. was added a solution of alcohol (119) (4.50 g, 21.22 mmol)in dry THF (50 mL). The resulting mixture was stirred for 5 h at 0° C.,then overnight at room temperature. The mixture was concentrated invacuo and the residue was partitioned with water and ethylacetate/hexane. The organic layer was separated and washed withsaturated NH₄Cl, brine, and dried over Na₂SO₄. After filtration andconcentration, the crude product was purified by flash chromatography onsilica gel, eluting with 20% ethyl acetate in hexane to afford 2.6 g ofthe title compound. ¹H-NMR (CDCl₃, 400 MHz): δ 2.48 (s, 3H), 5.27 (s,2H), 7.37 (br, s, 5H).

Step D: 5-Methyl-2-Oxo-1,3-Dioxol-4-enyl-4-Carboxylic Acid (121)

To a solution of compound (120) (2.6 g, 10.92 mmol) in 50 mL of ethanolwas added 260 mg of Pd/C (5%) and the resulting mixture was stirredunder a hydrogen atmosphere for 1 h. Filtration and removal of solventunder reduced pressure provided 1.62 g of the title compound. ¹H-NMR(CD₃OD, 400 MHz): δ 2.41 (s, 3H).

Step E: 4-Hydroxymethyl-5-Methyl-2-Oxo-1,3-Dioxol-4-ene (122)

To a solution of the acid (121) (1.62 g, 11.10 mmol) and anhydrous DMF(112 μL) in dry dichloromethane (50 mL) at 0° C. was dropwise addedoxalyl chloride (6.1 mL of 2M solution, 12.2 mmol). After stirring for30 min at 0° C. and 1 h at room temperature, the solvent was removedunder reduced pressure. The residue was dissolved in anhydrousdichloromethane (65 mL) and cooled to −78° C. To this solution wasdropwise added a solution of Bu₄NBH₄ (3.14 g, 12.2 mmol, in 20 mLdichloromethane) over 10 min. After stirring for 1 h at −78° C., themixture was cautiously quenched with 0.1N HCl (30 mL) and allowed towarm to room temperature. The aqueous layer was separated and wasextracted with EtOAc (3×50 mL) and the combined organic extract waswashed with brine and dried over Na₂SO₄. After removing the solventunder reduced pressure, column chromatography on silica gel, elutingwith 50% EtOAc in dichloromethane provided 767 mg of the title compound.¹H-NMR (CD₃OD, 400 MHz): δ 2.09 (s, 3H), 4.34 (s, 2H).

Step F: Benzyl1-{[((5-Methyl-2-Oxo-1,3-Dioxol-4-en-4-yl)methoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetate (123)

A suspension of the alcohol (122) (767 mg, 5.9 mmol) and benzyl1-isocyanatomethyl-1-cyclohexane acetate (5.9 mmol) in toluene wasrefluxed overnight. After removing the solvent under reduced pressure,the residue was purified by flash column chromatography, eluting with30% EtOAc in hexane to provide 510 mg of the title compound. ¹H-NMR(CD₃OD, 400 MHz): δ 1.58-1.30 (m, 10H), 2.18 (s, 3H), 2.35 (s, 2H), 3.17(d, J=6.8 Hz, 2H), 4.80 (s, 2H), 5.11 (s, 2H), 5.44 (t, J=6.8 Hz, 1H),7.36 (m, 5H).

Step G:1-{[((5-Methyl-2-Oxo-1,3-Dioxol-4-en-4-yl)methoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetic Acid (117)

To a solution of compound (123) (510 mg, 1.41 mmol) in ethanol (20 mL)was added 59 mg of Pd/C (5%) and the resulting mixture was stirred undera hydrogen atmosphere for 1 h. Filtration and removal of volatiles underreduced pressure provided the crude product, which was purified bypreparative LC/MS to provide 105 mg of the title compound. ¹H-NMR(CD₃OD, 400 MHz): δ 1.52-1.36 (m, 10H), 2.16 (s, 3H), 2.27 (s, 2H), 3.22(s, 2H), 4.86 (s, 2H).

Example 36 Piperidinium1-{(1-Methyl-3-Oxo-But-1-enyl)aminomethyl}-1-Cyclohexane Acetate (124)

2,4-pentanedione (103 μL, 1 mmol), gabapentin (171 mg, 1 mmol), andpiperidine (99 μL, 1 mmol) were mixed in anhydrous methanol (10 mL). Theresulting mixture was heated under reflux for 4 h. Removal of thesolvent under reduced pressure gave the title compound with puritygreater than 90%. ¹H NMR (CDCl₃, 400 MHz): δ 1.34-1.62 (m, 12H), 1.71(m, 4H), 1.94 (s, 3H), 1.96 (s, 3H), 2.26 (s, 2H), 2.98 (m, 4H), 3.38(d, J=6 Hz, 2H), 4.90 (s, 1H), 5.20 (s, br, 2H), 8.64 (t, J=6 Hz, 1H).MS (ESI) m/z 252.35 (M−H⁻).

Example 37 Piperidinium1-{1-[(2-Oxo-Tetrahydrofuran-3-ylidene)ethyl]aminomethyl}-1-CyclohexaneAcetate (125)

2-Acetylbutyrolactone (108 μL, 1 mmol), gabapentin (171 mg, 1 mmol), andpiperidine (99 μL, 1 mmol) were mixed in anhydrous methanol (10 mL).After heating under reflux for 6 h, the solvent was removed underreduced pressure to afford the title compound with purity greater than90%. ¹H NMR (CDCl₃, 400 MHz): δ 1.34-1.62 (m, 12H), 1.71 (m, 4H), 1.94(s, 3H), 2.24 (s, 2H), 2.81 (t, J=7.6 Hz, 2H), 2.99 (m, 4H), 3.31 (d,J=6.4 Hz, 2H), 4.23 (t, J=7.6 Hz, 2H), 5.17 (s, br, 2H), 8.64 (t, J=6.4Hz, 1H). MS (ESI) m/z 280.34 (M−H⁻).

Example 38 Piperidinium1-{(2-Carbomethoxy-Cyclopent-1-enyl)aminomethyl}-1-Cyclohexane Acetate(126)

Methyl 2-oxocyclopentanecarboxylate (124 μL, 1 mmol), gabapentin (171mg, 1 mmol), and piperidine (99 μL, 1 mmol) were mixed in anhydrousmethanol (10 mL). After heating under reflux for 16 h, the solvent wasremoved under reduced pressure to afford the title compound with puritygreater than 90%. ¹H NMR (CDCl₃, 400 MHz): δ 1.29-1.60 (m, 12H), 1.72(m, 4H), 1.79 (m, J=7.6 Hz, 2H), 2.24 (s, 2H), 2.49 (t, J=7.6 Hz, 2H),2.55 (t, J=7.6 Hz, 2H), 2.99 (m, 4H), 3.24 (d, J=6.8 Hz, 2H), 3.63 (s,3H), 5.06 (s, br, 2H), 7.93 (s, br, 1H). MS (ESI) m/z 294.36 (M−H⁻).

Example 39 Piperidinium1-{(1-Methyl-2-(Ethoxycarbonyl)-3-Ethoxy-3-Oxoprop-1-enyl)aminomethyl}-1-CyclohexaneAcetate (127)

Diethyl acetylmalonate (202 mg, 1 mmol), gabapentin (171 mg, 1 mmol),and piperidine (99 μL, 1 mmol) were mixed in anhydrous ethanol (10 mL).After heating under reflux for 16 h, the solvent was removed underreduced pressure to give the title compound with purity greater than90%. ¹H NMR (CDCl₃, 400 MHz): δ 1.28 (t, J=7.2 Hz, 6H), 1.38-1.64 (m,12H), 1.75 (m, 4H), 1.96 (s, 3H), 2.23 (s, 2H), 2.99 (m, 4H), 3.24 (d,J=5.2 Hz, 2H), 4.20 (q, J=7.2 Hz, 4H), 4.35 (s, br, 2H), 7.79 (t, J=5.2Hz, 1H). MS (ESI) m/z 354.38 (M−H⁻).

Example 401-{[(α-(2-(2-Methyl-1,3-Dioxolan-2-yl)carboxyisobutoxy)carbonyl]-aminomethyl}-1-CyclohexaneAcetic Acid (128)

Step A: 2-Methyl-1,3-Dioxolane-2-Carboxylic Acid (129)

To a stirred mixture containing ethyl pyruvate (11.1 mL, 0.1 mol) andethylene glycol (5.6 mL, 0.1 mol) in anhydrous dichloromethane (100 mL)at 0° C. was added boron trifluoride dietherate (6.4 mL, 0.05 mol) andcatalytic amount of acetic acid. The resulting mixture was stirred at40° C. for 16 h and then diluted with 100 mL of dichloromethane. Theorganic solution was washed successively with saturated sodium chloridesolution (2×80 mL). The organic layer was separated and the combinedorganic extracts were concentrated. The residue was treated with 1Nsodium hydroxide at room temperature. After stirring at room temperaturefor 3 h (monitored by TLC), citric acid was added to adjust the pH to 4.The product was extracted with dichloromethane, dried over Na₂SO₄ andconcentrated to afford 5.1 g (38%) of the title compound (129) as aclear liquid. This material was used in the next reaction withoutfurther purification. ¹H NMR (CDCl₃, 400 MHz): δ 1.55 (s, 3H), 4.03 (m,4H).

Step B: Benzyl1-{[(α-(2-(2-Methyl-1,3-Dioxolan-2-yl)carboxyisobutoxy)carbonyl]aminomethyl}-1-CyclohexaneAcetate (130)

A mixture containing benzyl1-{[(α-chloroisobutoxy)carbonyl]aminomethyl}-1-cyclohexane acetate (95)(1 g, 2.53 mmol), (129) (673 mg, 5.1 mmol), silver carbonate (557 mg,2.53 mmol), and triethylamine (709 μL, 5.1 mmol) in chloroform wasstirred at room temperature for 16 h. After filtration, the filtrate wasconcentrated. The resulting residue was purified by silica gelchromatography, eluting with 15% ethyl acetate/hexane to afford 510 mg(41%) of the title compound (130). MS (ESI) m/z 492.40 (M+H⁺).

Step C:1-{[(α-(2-(2-Methyl-1,3-Dioxolan-2-yl)carboxyisobutoxy)carbonyl]-aminomethyl}-1-CyclohexaneAcetic Acid (128)

A mixture of (130) (470 mg, 0.96 mmol) and 5% Pd—C (catalytic amount) inethanol was stirred under hydrogen at room temperature for 16 h.Filtration and concentration gave 382 mg (100%) of the title compound(128). ¹H NMR (CDCl₃, 400 MHz): δ 0.96 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8Hz, 3H), 1.32-1.58 (m, 10H), 1.59 (s, 3H), 2.06 (m, 1H), 2.32 (s, 2H),3.26 (m, 2H), 4.08 (m, 4H), 5.29 (t, 1H, NH), 6.55 (d, J=4.8 Hz, 1H). MS(ESI) m/z 402.32 (M+H⁺).

The acid form was quantitatively converted to its corresponding sodiumsalt by dissolution in water (5 mL), addition of an equimolar quantityof 0.5 N NaHCO₃, followed by lyophilization.

Example 41 In Vitro Determination of Caco-2 Cellular Permeability ofProdrugs

The passive permeability of the prodrugs of the current invention may beassessed in vitro using standard methods well known in the art (See,e.g., Stewart, et al., Pharm. Res., 1995, 12, 693). For example, passivepermeability may be evaluated by examining the flux of a prodrug acrossa cultured polarized cell monolayer (e.g., Caco-2 cells). Caco-2 cellsobtained from continuous culture (passage less than 28) were seeded athigh density onto Transwell polycarbonate filters. Cells were maintainedwith DMEM/10% fetal calf serum+0.1 mM nonessential amino acids+2 mML-Gln, 5% CO₂/95% O₂, 37° C. until the day of the experiment.Permeability studies were conducted at pH 6.5 apically (in 50 mM MESbuffer containing 1 mM CaCl₂, 1 mM MgCl₂, 150 mM NaCl, 3 mM KCl, 1 mMNaH₂PO4, 5 mM glucose) and pH 7.4 basolaterally (in Hanks' balanced saltsolution containing 10 mM HEPES) in the presence of efflux pumpinhibitors (250 μM MK-571, 250 uM Verapamil, 1 mM Ofloxacin). Insertswere placed in 12 or 24 well plates containing buffer and incubated for30 min at 37° C. Prodrug (200 μM) was added to the apical or basolateralcompartment (donor) and concentrations of prodrug and/or released parentdrug in the opposite compartment (receiver) were determined at intervalsover 1 hour using LC/MS/MS. Values of apparent permeability (P_(app))were calculated using the equation:

 P _(app) =V _(r)(dC/dt)//(AC _(o))

Here V_(r) is the volume of the receiver compartment in mL; dC/dt is thetotal flux of prodrug and parent drug (μM/s), determined from the slopeof the plot of concentration in the receiver compartment versus time;C_(o) is the initial concentration of prodrug in μM; A is the surfacearea of the membrane in cm². Preferably, prodrugs with significanttranscellular permeability demonstrate a value of P_(app) of ≧1×10⁻⁶cm/s and more preferably, a value of P_(app) of ≧1×10⁻⁵ cm/s, and stillmore preferably a value of P_(app) of >5×10⁻⁵ cm/s. Typical values ofP_(app) obtained for prodrugs of GABA analogs are shown in the followingtable:

P_(app) (apical to P_(app) (basolateral to Ratio Compound basolateral)(cm/s) apical) (cm/s) A-B/B-A (51) 1.06 × 10⁻⁴ 1.25 × 10⁻⁵ 8.5 (56)  3.1× 10⁻⁵  2.0 × 10⁻⁶ 15.5 (62) 2.10 × 10⁻⁵ 6.40 × 10⁻⁶ 3.3 (68) 8.43 ×10⁻⁵ 2.26 × 10⁻⁵ 3.7 (69) 1.84 × 10⁻⁴ 5.22 × 10⁻⁶ 35.2 (70) 1.78 × 10⁻⁵1.68 × 10⁻⁶ 10.6 (71) 8.10 × 10⁻⁵ 1.99 × 10⁻⁵ 4.1 (72) 2.51 × 10⁻⁵ 1.26× 10⁻⁶ 2.0 (77) 7.41 × 10⁻⁵ 1.43 × 10⁻⁵ 5.2 (78) 1.37 × 10⁻⁴ 2.46 × 10⁻⁵5.6 (80) 6.62 × 10⁻⁵ 8.75 × 10⁻⁶ 7.6 (81) 8.65 × 10⁻⁵ 1.27 × 10⁻⁵ 6.8(82) 1.25 × 10⁻⁴ 1.82 × 10⁻⁵ 6.9 (83) 1.29 × 10⁻⁵ 4.48 × 10⁻⁵ 0.3 (84)1.26 × 10⁻⁴ 1.57 × 10⁻⁵ 8.1 (89) 5.85 × 10⁻⁵ 2.34 × 10⁻⁶ 25.0 (90) 9.22× 10⁻⁵ 5.75 × 10⁻⁶ 16.0

The data in this table shows that the prodrugs disclosed herein havehigh cellular permeability and should be well absorbed from theintestine. With the exception of compound (83), theapical-to-basolateral permeabilities of these prodrugs exceed theirbasolateral-to-apical permeabilities. This suggests that these compoundsmay be substrates for active transport mechanisms present in the apicalmembrane of Caco cells (though some component of this transcellularpermeability may also be mediated by passive diffusion). The greaterbasolateral-to-apical permeability of (83) suggests that this compoundmay be subject to efflux across the basolateral membrane, despite thepresence of the efflux pump inhibitors MK-571, verapamil and ofloxacin.

Example 42 Uptake of Gabapentin Following Administration of Gabapentinor Gabapentin Prodrugs Intracolonically in Rats

Sustained release oral dosage forms, which release drug slowly overperiods of 6-24 hours, generally release a significant proportion of thedose within the colon. Thus drugs suitable for use in such dosage formspreferably exhibit good colonic absorption. This experiment wasconducted to assess the suitability of gabapentin prodrugs for use in anoral sustained release dosage form.

Step A: Administration Protocol

Rats were obtained commercially and were pre-cannulated in the both theascending colon and the jugular vein. Animals were conscious at the timeof the experiment. All animals were fasted overnight and until 4 hourspost-dosing. Gabapentin or gabapentin prodrugs (59), (63), (69), (72),(77), (79), (85), (117) and (126) were administered as a solution (inwater or PEG 400) directly into the colon via the cannula at a doseequivalent to 25 mg of gabapentin per kg. Blood samples (0.5 mL) wereobtained from the jugular cannula at intervals over 8 hours and werequenched immediately by addition of acetonitrile/methanol to preventfurther conversion of the prodrug. Blood samples were analyzed asdescribed below.

Step B: Sample Preparation for Colonic Absorbed Drug

-   -   1. In blank 1.5 mL eppendorf tubes, 300 μL of 50/50        acetonitrile/methanol and 20 μL of p-chlorophenylalanine was        added as an internal standard.    -   2. Rat blood was collected at different time points and        immediately 100 μL of blood was added into the eppendorf tube        and vortexed to mix.    -   3. 10 μL of a gabapentin standard solution (0.04, 0.2, 1, 5, 25,        100 μg/mL) was added to 90 μL of blank rat blood to make up a        final calibration standard (0.004, 0.02, 0.1, 0.5, 2.5, 10        μg/mL). Then 300 μL of 50/50 acetonitrile/methanol was added        into each tube followed by 20 μL of p-chlorophenylalanine.    -   4. Samples were vortexed and centrifuged at 14,000 rpm for 10        min.    -   5. Supernatant was taken for LC/MS/MS analysis.        Step C: LC/MS/MS Analysis

An API 2000 LC/MS/MS spectrometer equipped with Shidmadzu 10ADVp binarypumps and a CTC HTS-PAL autosampler were used in the analysis. A ZorbaxXDB C8 4.6×150 mm column was heated to 45° C. during the analysis. Themobile phase was 0.1% formic acid (A) and acetonitrile with 0.1% formicacid (B). The gradient condition was: 5% B for 1 min, then to 98% B in 3min, then maintained at 98% B for 2.5 min. The mobile phase was returnedto 5% B for 2 min. A TurbolonSpray source was used on the API 2000. Theanalysis was done in positive ion mode and an MRM transition of 172/137was used in the analysis of gabapentin (MRM transitions 426/198 for(59), 364/198 for (63), 392/198 for (69), 316/198 for (72), 330/198 for(77), 330/198 for (79), 316/198 for (85) and 327.7/153.8 for (117) wereused). 20 μL of the samples were injected. The peaks were integratedusing Analyst 1.1 quantitation software. Following colonicadministration of each of these prodrugs, the maximum plasmaconcentrations of gabapentin (C_(max)), as well as the area under thegabapentin plasma concentration vs. time curves (AUC) were significantlygreater (>2-fold) than that produced from colonic administration ofgabapentin itself. For example, prodrug (77) provided both gabapentinC_(max) and AUC values greater than 10-fold higher than gabapentinitself. This data demonstrates that compounds of the invention may beformulated as compositions suitable for enhanced absorption and/oreffective sustained release of GABA analogs to minimize dosing frequencydue to rapid systemic clearance of these GABA analogs.

Example 43 Sustained Release of Gabapentin Following ProdrugAdministration Using Osmotic Mini-Pump Devices in Beagle Dogs

Gabapentin or the gabapentin prodrugs (77) and (82) (at a doseequivalent to 10 mg of gabapentin per kg) were dissolved in a suitablesolvent (e.g., water, PEG 400, etc.) and filled into preweighed Alzet®mini-osmotic pump devices (Model 2001D) (Durect Corp., Cupertino,Calif.). The filled Alzets were pre-equilibrated by soaking in isotonicsaline at 37° C. for 3 hours and stored in sealed containers at 4° C.overnight. Alzets were then administered orally to four fasted malebeagle dogs (approx. 6.5 kg). Animals were fed at 4 hr after each dose.Blood samples (1.0 mL) were withdrawn at intervals over 48 hours andprocessed immediately for plasma. Plasma samples were frozen and storedat −80° C. until analyzed using the method described above. Bothprodrugs afforded gabapentin concentrations in plasma at 12 hourspost-dosing that were greater than 2-fold the concentration ofgabapentin seen following administration of gabapentin itself in theAlzet device. This data further confirms that compounds of the inventionmay be formulated as compositions suitable for effective sustainedrelease of GABA analogs.

Example 44 Uptake of Pregabalin Following Administration of Pregabalinor Pregabalin Prodrugs Intracolonically in Rats

The protocol of Example 41 was repeated with pregabalin and thepregabalin prodrugs (110) and (112). Following colonic administration ofeach of these prodrugs, the maximum plasma concentrations of pregabalin(C_(max)), as well as the area under the pregabalin plasma concentrationvs. time curves (AUC) were significantly greater (>2-fold) than thatproduced from colonic administration of pregabalin itself.

Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by referencein their entirety.

1. A compound of formula:

or a pharmaceutically acceptable salt, hydrate or solvate thereofwherein: R⁷ and R¹⁴ are each hydrogen; R¹³ is selected from the groupconsisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl andsec-butyl; and R²⁵ is selected from the group consisting of methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl and 1,1-diethoxyethyl.
 2. The compoundof claim 1 wherein R¹³ is methyl.
 3. The compound of claim 1, whereinR²⁵ is methyl, ethyl, n-propyl or isopropyl.
 4. The compound of claim 1,wherein R¹³ is methyl and R²⁵ is methyl, ethyl, n-propyl or n-butyl. 5.The compound of claim 1, wherein R¹³ is ethyl and R²⁵ is methyl,n-propyl or isopropyl.
 6. The compound of claim 1, wherein R¹³ isn-propyl and R²⁵ is methyl, ethyl, n-propyl, isopropyl or n-butyl. 7.The compound of claim 1, wherein R¹³ is isopropyl and R²⁵ is methyl,ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
 8. The compound ofclaim 1, wherein R¹³ is n-propyl and R²⁵ is n-propyl.
 9. The compound ofclaim 1, wherein R¹³ is methyl and R²⁵ is ethyl.
 10. The compound ofclaim 1, wherein R¹³ is methyl and R¹⁵ is isopropyl.
 11. The compound ofclaim 1, wherein R¹³ is isopropyl and R²⁵ is isopropyl.
 12. The compoundof claim 1, wherein R¹³ is isopropyl and R²⁵ is 1,1-diethoxyethyl. 13.The compound of claim 1, wherein R¹³ is propyl and R²⁵ is isopropyl. 14.The compound of claim 1, wherein R¹³ is propyl and R²⁵ is ethyl.